Advertisement

Pharmacologic Therapies for Severe Asthma

  • So Ri Kim
Chapter

Abstract

To date, pharmacologic treatments for asthma are predominantly nonspecific anti-inflammatory agents such as corticosteroid and bronchodilators including β2 agonists, which are effective in the majority of patients with asthma. However, therapeutic responses to these agents vary. Severe asthma is characterized by uncontrolled symptoms and recurrent exacerbation with excessive chronic airway inflammation despite adequate and even maximum treatment with these current medications. Although multiple factors can cause poor responses and underlying pathogenic differences are being revealed explaining the various therapeutic responses including steroid insensitivity, effective therapeutic modalities for severe asthma still remained as a major unmet need. Moreover, new members of pharmacological therapeutics and more effective drug-delivery devices (i.e., inhaled device) have been designed, but the proportion of severe asthmatic patients remains stable. Considering nowadays concept of severe asthma, heterogeneity, the improvement of the characterization of the patients is required to achieve appropriate therapeutic responses for severe asthma. It is expected that the determination of phenotype and endotype leads to more effective precision medicine. In this chapter, recent advances in pharmacologic treatment of severe asthma will be introduced including improved current medications, potent nonspecific anti-inflammatory agents, endotype-targeted treatments, specific treatment for comorbidities, and potential therapeutic candidates.

Keywords

Corticosteroids Bronchodilator Kinase inhibitors ER stress inhibitors Mitochondria-targeting antioxidants PDE4 inhibitors Type 2 targeting agents Non-type 2 targeting agents Clinical comorbidities 

References

  1. 1.
    Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (updated 2017). 2017. http://www.ginasthma.org. Accessed 5 May 2017.
  2. 2.
    Adams NP, Bestall JC, Jones P, Lasserson TJ, Griffiths B, Cates CJ, et al. Fluticasone at different doses for chronic asthma in adults and children. Cochrane Database Syst Rev. 2008;4:CD003534.Google Scholar
  3. 3.
    Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med. 2004;170(8):836–44.PubMedCrossRefGoogle Scholar
  4. 4.
    Cates CJ, Lasserson TJ. Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev. 2009;2:CD007313.Google Scholar
  5. 5.
    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
  6. 6.
    Nave R. Clinical pharmacokinetic and pharmacodynamic profile of inhaled ciclesonide. Clin Pharmacokinet. 2009;48(4):243–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Gentile DA, Skoner DP. New asthma drugs: small molecule inhaled corticosteroids. Curr Opin Pharmacol. 2010;10(3):260–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Contoli M, Bousquet J, Fabbri LM, Magnussen H, Rabe KF, Siafakas NM, et al. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy. 2010;65(2):141–51.PubMedCrossRefGoogle Scholar
  9. 9.
    Hodgson D, Anderson J, Reynolds C, Meakin G, Bailey H, Pavord I, et al. A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA). Thorax. 2015;70(6):559–65.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Biggadike K. Fluticasone furoate/fluticasone propionate—different drugs with different properties. Clin Respir J. 2011;5(3):183–4.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Allen A, Pierre LN, Rousell VM. Fluticasone furoate (FF) a novel inhaled corticosteroid demonstrates prolonged lung absorption kinetics in man. Am J Respir Crit Care Med. 2010;181:A5408.Google Scholar
  12. 12.
    van den Berge M, Luijk B, Bareille P, Dallow N, Postma DS, Lammers JW, et al. Prolonged protection of the new inhaled corticosteroid fluticasone furoate against AMP hyperresponsiveness in patients with asthma. Allergy. 2010;65(12):1531–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Keith PK, Scadding GK. Are intranasal corticosteroids all equally consistent in managing ocular symptoms of seasonal allergic rhinitis? Curr Med Res Opin. 2009;25(8):2021–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Gueron B, Demoly P, Piercy J, Small M. Do patients on intranasal fluticasone furoate, mometasone furoate and fluticasone propionate experience similar numbers of symptom-free days and quality of life? A cross-sectional study in three European countries. Allergy 2010;65 (Suppl 92):156.Google Scholar
  15. 15.
    Okobu K, Nakashima M, Miyake N, Komatsubara M, Okuda M. Comparison of fluticasone furoate and fluticasone propionate for the treatment of Japanese cedar pollinosis. Allergy Asthma Proc. 2009;30(1):84–94.CrossRefGoogle Scholar
  16. 16.
    Woodcock A, Bleecker ER, Lötvall J, O'Byrne PM, Bateman ED, Medley H, et al. Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma. Chest. 2013;144(4):1222–9.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Schacke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol Cell Endocrinol. 2007;275(1–2):109–17.PubMedCrossRefGoogle Scholar
  18. 18.
    De Bosscher K. Selective glucocorticoid receptor modulators. J Steroid Biochem Mol Biol. 2010;120(2–3):96–104.PubMedCrossRefGoogle Scholar
  19. 19.
    Cazzola M, Coppola A, Rogliani P, Matera MG. Novel glucocorticoid receptor agonists in the treatment of asthma. Expert Opin Investig Drugs. 2015;24(11):1473–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Rossi A, van der Molen T, del Olmo R, Papi A, Wehbe L, Quinn M, del Olmo R, et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J. 2014;44(6):1548–56.PubMedCrossRefGoogle Scholar
  21. 21.
    Ferguson GT, Feldman GJ, Hofbauer P, Hamilton A, Allen L, Korducki L, et al. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies. Int J Chron Obstruct Pulmon Dis. 2014;9:629–45.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B, et al. Long-term safety and efficacy of indacaterol, a long-acting β2-agonist, in subjects with COPD: a randomized, placebo-controlled study. Chest. 2011;140(1):68–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Hanania NA, Feldman G, Zachgo W, Shim JJ, Crim C, Sanford L, et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142(1):119–27.PubMedCrossRefGoogle Scholar
  24. 24.
    Beasley RW, Donohue JF, Mehta R, Nelson HS, Clay M, Moton A, et al. Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial. BMJ Open. 2015;5(2):e006131.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Raemdonck K, de Alba J, Birrell MA, Grace M, Maher SA, Irvin CG, et al. A role for sensory nerves in the late asthmatic response. Thorax. 2012;67(1):19–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Kummer W, Lips KS, Pfeil U. The epithelial cholinergic system of the airways. Histochem Cell Biol. 2008;130(2):219–34.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, Gross NJ, et al. Alternative mechanisms for tiotropium. Pulm Pharmacol Ther. 2009;22(6):533–42.PubMedCrossRefGoogle Scholar
  28. 28.
    Ohta S, Oda N, Yokoe T, Tanaka A, Yamamoto Y, Watanabe Y, et al. Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma. Clin Exp Allergy. 2010;40(8):1266–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Bos IS, Gosens R, Zuidhof AB, Schaafsma D, Halayko AJ, Meurs H, et al. Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. Eur Respir J. 2007;30(4):653–61.PubMedCrossRefGoogle Scholar
  30. 30.
    Park HW, Yang MS, Park CS, Kim TB, Moon HB, Min KU, et al. Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response. Allergy. 2009;64(5):778–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Kerstjens HA, Disse B, Schroder-Babo W, Bantje TA, Gahlemann M, Sigmund R, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011;128(2):308–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715–26.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM, et al. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011;128(2):315–22.PubMedCrossRefGoogle Scholar
  34. 34.
    Kerstjens HAM, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–207.PubMedCrossRefGoogle Scholar
  35. 35.
    Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (updated 2016). 2016. http://www.ginasthma.org. Accessed 5 May 2017.
  36. 36.
    Hansel TT, Neighbour H, Erin EM, Tan AJ, Tennant RC, Maus JG, et al. Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma. Chest. 2005;128(4):1974–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Lee LA, Briggs A, Edwards LD, Yang S, Pascoe S. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015;109(1):63–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee LA, Yang S, Kerwin E, Trivedi R, Edwards LD, Pascoe S, et al. The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. Respir Med. 2015;109(1):54–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Adcock IM, Chung KF, Caramori G, Ito L. Kinase inhibitors and airway inflammation. Eur J Pharmacol. 2006;533(1–3):118–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012;129(1):48–59.PubMedCrossRefGoogle Scholar
  41. 41.
    Mercado N, Hakim A, Kobayashi Y, Meah S, Usmani OS, Chung KF, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor function via phosphorylation. Ann N Y Acad Sci. 2004;1024:86–101.PubMedCrossRefGoogle Scholar
  43. 43.
    Loke TK, Mallett KH, Ratoff J, O’Connor BJ, Ying S, Meng Q, 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):368–75.PubMedCrossRefGoogle Scholar
  44. 44.
    Goleva E, Kisich KO, Leung DY. A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance. J Immunol. 2002;169(10):5934–40.PubMedCrossRefGoogle Scholar
  45. 45.
    To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T, et al. Targeting phosphoinositide-3-kinase-d with theophylline reverses corticosteroid insensitivity in COPD. Am J Respir Crit Care Med. 2010;182(7):897–904.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bhavsar P, Hew M, Khorasani N, Alfonso T, Barnes PJ, Adcock I, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared to non-severe asthma. Thorax. 2008;63(9):784–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905–17.PubMedCrossRefGoogle Scholar
  48. 48.
    Sher ER, Leung DY, Surs W, Kam JC, Zieg G, Kamada AK, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest. 1994;93(1):33–9.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM, et al. p38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol. 2002;109(4):649–57.PubMedCrossRefGoogle Scholar
  50. 50.
    Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773(8):1358–75.PubMedCrossRefGoogle Scholar
  51. 51.
    Hammaker D, Firestein GS. “Go upstream, young man”: lessons learned from the p38 saga. Ann Rheum Dis. 2010;69(Suppl 1):i77–82.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Duan W, Chan JH, McKay K, Crosby JR, Choo HH, Leung BP, et al. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med. 2005;171(6):571–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Millan DS, Bunnage ME, Burrows JL, Butcher KJ, Dodd PG, Evans TJ, et al. Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J Med Chem. 2011;54(22):7797–814.PubMedCrossRefGoogle Scholar
  54. 54.
    Kim SR, Lee KS, Park SJ, Min KH, Lee MH, Lee KA, et al. A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase. Am J Respir Crit Care Med. 2011;183(8):1015–524.PubMedCrossRefGoogle Scholar
  55. 55.
    Barnes PJ. Therapeutic approaches to asthma–chronic obstructive pulmonary disease overlap syndromes. J Allergy Clin Immunol. 2015;136(3):531–45.PubMedCrossRefGoogle Scholar
  56. 56.
    Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kB, in asthma. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1585–92.PubMedCrossRefGoogle Scholar
  57. 57.
    Caramori G, Romagnoli M, Casolari P, Bellettato C, Casoni G, Boschetto P, et al. Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax. 2003;58(4):348–51.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Lee YC, Lee KS, Park SJ, Park HS, Lim JS, Park KH, et al. Blockade of airway hyperresponsiveness and inflammation in a murine model of asthma by a prodrug of cysteine, L-2-oxothiazolidine-4-carboxylic acid. FASEB J. 2004;18(15):1917–9.PubMedGoogle Scholar
  59. 59.
    Lee KS, Kim SR, Park SJ, Park HS, Min KH, Jin SM, et al. Peroxisome proliferator activated receptor-gamma modulates reactive oxygen species generation and activation of nuclear factor-kappaB and hypoxia-inducible factor 1alpha in allergic airway disease of mice. Allergy Clin Immunol. 2006;118(1):120–7.CrossRefGoogle Scholar
  60. 60.
    Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Jin SM, et al. Antioxidant down-regulates interleukin-18 expression in asthma. Mol Pharmacol. 2006;70(4):1184–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee KS, Kim SR, Park HS, Park SJ, Min KH, Lee KY, et al. A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha. Exp Mol Med. 2007;39(6):756–68.PubMedCrossRefGoogle Scholar
  62. 62.
    Park SJ, Lee KS, Lee SJ, Kim SR, Park SY, Jeon MS, et al. L-2-Oxothiazolidine-4-carboxylic acid or α-lipoic acid attenuates airway remodeling: involvement of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF). Int J Mol Sci. 2012;13(7):7915–37.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kim SR, Kim DI, Kim SH, Lee H, Lee KS, Cho SH, et al. NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation. Cell Death Dis. 2014;5:e1498.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Kim SR, Kim DI, Kang MR, Lee KS, Park SY, Jeong JS, et al. Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation. J Allergy Clin Immunol. 2013;132(6):1397–408.PubMedCrossRefGoogle Scholar
  65. 65.
    Kwak YG, Song CH, Yi HK, Hwang PH, Kim JS, Lee KS, et al. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma. J Clin Invest. 2003;111(7):1083–92.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lee KS, Park SJ, Kim SR, Min KH, Jin SM, Puri KD, et al. Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma. J Allergy Clin Immunol. 2006;118(2):403–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim SR, Lee KS, Park SJ, Min KH, Lee KY, Choe YH, et al. PTEN down-regulates IL-17 expression in a murine model of toluene diisocyanate-induced airway disease. J Immunol. 2007;179(10):6820–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Lee KS, Park SJ, Kim SR, Min KH, Lee KY, Choe YH, et al. Inhibition of VEGF blocks TGF-beta1 production through a PI3K/Akt signalling pathway. Eur Respir J. 2008;31(3):523–31.PubMedCrossRefGoogle Scholar
  69. 69.
    Lee KS, Kim SR, Park SJ, Min KH, Lee KY, Choe YH, et al. Mast cells can mediate vascular permeability through regulation of the PI3K-HIF-1alpha-VEGF axis. Am J Respir Crit Care Med. 2008;178(8):787–97.PubMedCrossRefGoogle Scholar
  70. 70.
    Park SJ, Min KH, Lee YC. Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma. Respirology. 2008;13(6):764–71.PubMedCrossRefGoogle Scholar
  71. 71.
    Kim SR, Lee KS, Park HS, Park SJ, Min KH, Moon H, et al. HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. Eur J Immunol. 2010;40(10):2858–69.PubMedCrossRefGoogle Scholar
  72. 72.
    Kim DI, Kim SR, Kim HJ, Lee SJ, Lee HB, Park SJ, et al. PI3K-γ inhibition ameliorates acute lung injury through regulation of IκBα/NF-κB pathway and innate immune responses. J Clin Immunol. 2012;32(2):340–51.PubMedCrossRefGoogle Scholar
  73. 73.
    Lee KS, Jeong JS, Kim SR, Cho SH, Kolliputi N, Ko YH, et al. Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress. Thorax. 2016;71(1):52–63.PubMedCrossRefGoogle Scholar
  74. 74.
    Horak F, Puri KD, Steiner BH, Holes L, Xing G, Zieglmayer P, et al. Randomized phase 1 study of the phosphatidylinositol 3-kinase δ inhibitor idelalisib in patients with allergic rhinitis. J Allergy Clin Immunol. 2016;137(6):1733–41.PubMedCrossRefGoogle Scholar
  75. 75.
    Nohl H, Kozlov AV, Gille L, Staniek K. Cell respiration and formation of reactive oxygen species: facts and artefacts. Biochem Soc Trans. 2003;31(Pt 6):1308–11.PubMedCrossRefGoogle Scholar
  76. 76.
    Liu PL, Chen YL, Chen YH, Lin SJ, Kou YR. Wood smoke extract induces oxidative stress-mediated caspase-independent apoptosis in human lung endothelial cells: role of AIF and EndoG. Am J Physiol Lung Cell Mol Physiol. 2005;289(5):L739–49.PubMedCrossRefGoogle Scholar
  77. 77.
    Vayssier-Taussat M, Camilli T, Aron Y, Meplan C, Hainaut P, Polla BS, et al. Effects of tobacco smoke and benzo[a]pyrene on human endothelial cell and monocyte stress responses. Am J Physiol Heart Circ Physiol. 2001;280(3):H1293–300.PubMedGoogle Scholar
  78. 78.
    Wilson MR, Lightbody JH, Donaldson K, Sales J, Stone V. Interactions between ultrafine particles and transition metals in vivo and in vitro. Toxicol Appl Pharmacol. 2002;184(3):172–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Park HS, Kim SR, Kim JO, Lee YC. The roles of phytochemicals in bronchial asthma. Molecules. 2010;15(10):6810–34.PubMedCrossRefGoogle Scholar
  80. 80.
    Barnes PJ. Reactive oxygen species in asthma. Eur Respir Rev. 2000;10:240–3.Google Scholar
  81. 81.
    Lee KS, Kim SR, Park SJ, Park HS, Min KH, Lee MH, et al. Hydrogen peroxide induces vascular permeability via regulation of vascular endothelial growth factor. Am J Respir Cell Mol Biol. 2006;35(2):190–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Cho YJ, Seo MS, Kim JK, Lim Y, Chae G, Ha KS, et al. Silica-induced generation of reactive oxygen species in Rat2 fibroblasts: role in activation of mitogen-activated protein kinase. Biochem Biophys Res Commun. 1999;262(3):708–12.PubMedCrossRefGoogle Scholar
  83. 83.
    Ding M, Shi X, Dong Z, Chen F, Lu Y, Castranova V, et al. Freshly fractured crystalline silica induces activator protein-1 activation through ERKs and p38 MAPK. J Biol Chem. 1999;274(43):30611–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R. Linkage of G protein coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science. 1997;275(5298):394–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Lee KS, Park HS, Park SJ, Kim SR, Min KH, Jin SM, et al. An antioxidant modulates expression of receptor activator of NF-κB in asthma. Exp Mol Med. 2006;38(3):217–29.PubMedCrossRefGoogle Scholar
  86. 86.
    Schenk H, Klein M, Erdbrügger W, Dröge W, Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-κB and AP-1. Proc Natl Acad Sci U S A. 1994;91(5):1672–6.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Harper R, Wu K, Chang MM, Yoneda K, Pan R, Reddy SP, et al. Activation of nuclear factor-kappa b transcriptional activity in airway epithelial cells by thioredoxin but not by Nacetyl-cysteine and glutathione. Am J Respir Cell Mol Biol. 2001;25(2):178–85.PubMedCrossRefGoogle Scholar
  88. 88.
    Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4(5):E131–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Tikoo K, Lau SS, Monks TJ. Histone H2 phosphorylation is coupled to poly(ADPribosylation) during reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. Mol Pharmacol. 2001;60(2):394–402.PubMedGoogle Scholar
  90. 90.
    Zor U, Ferber E, Gergely P, Szücs K, Dombrádi V, Goldman R, et al. Reactive oxygen species mediate phorbol ester-regulated tyrosine phosphorylation and phospholipase A2 activation: potentiation by vanadate. Biochem J. 1993;295(Pt 3):879–88.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Goldman R, Ferber E, Zort U. Reactive oxygen species are involved in the activation of cellular phospholipase A2. FEBS Lett. 1992;309(2):190–2.PubMedCrossRefGoogle Scholar
  92. 92.
    Jaffer OA, Carter AB, Sanders PN, Dibbern ME, Winters CJ, Murthy S, et al. Mitochondrial-targeted antioxidant therapy decreases transforming growth factor-β-mediated collagen production in a murine asthma model. Am J Respir Cell Mol Biol. 2015;52(1):106–15.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Beghè B, Rabe KF, Fabbri LM. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am J Respir Crit Care Med. 2013;188(3):271–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Diamant Z, Spina D. PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther. 2011;24(4):353–60.PubMedCrossRefGoogle Scholar
  95. 95.
    Michalski JM, Golden G, Ikari J, Rennard SI. PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clin Pharmacol Ther. 2012;91(1):134–42.PubMedCrossRefGoogle Scholar
  96. 96.
    Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta analysis. Ther Adv Respir Dis. 2013;7(1):13–24.PubMedCrossRefGoogle Scholar
  97. 97.
    Gauvreau GM, Boulet LP, Schmid-Wirlitsch C, Côté J, Duong M, Killian KJ, et al. Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects. Respir Res. 2011;12:140.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Harbinson PL, MacLeod D, Hawksworth R, O’Toole S, Sullivan PJ, Heath P, et al. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects. Eur Respir J. 1997;10(5):1008–14.PubMedCrossRefGoogle Scholar
  99. 99.
    van Schalkwyk E, Strydom K, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, et al. Roflumilast, an oral, once daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol. 2005;116(2):292–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Louw C, Williams Z, Venter L, Leichtl S, Schmid-Wirlitsch C, Bredenbroker D, et al. Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge. Respiration. 2007;74(4):411–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Gauvreau GM, Evans MY. Allergen inhalation challenge: a human model of asthma exacerbation. Contrib Microbiol. 2007;14:21–32.PubMedCrossRefGoogle Scholar
  102. 102.
    Timmer W, Leclerc V, Birraux G, Neuhäuser M, Hatzelmann A, Bethke T, et al. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol. 2002;42(3):297–303.PubMedCrossRefGoogle Scholar
  103. 103.
    Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy. 2006;61(1):72–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10(22):1503–19.PubMedCrossRefGoogle Scholar
  105. 105.
    Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol. 2009;157(6):892–906.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29.PubMedCrossRefGoogle Scholar
  107. 107.
    Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–30.PubMedCrossRefGoogle Scholar
  108. 108.
    Toth A, Nickson P, Mandl A, Bannister ML, Toth K, Erhardt P, et al. Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. Cardiovasc Hematol Disord Drug Targets. 2007;7(3):205–18.PubMedCrossRefGoogle Scholar
  109. 109.
    Kelsen SG, Duan X, Ji R, Perez O, Liu C, Merali S, et al. Cigarette smoke induces an unfolded protein response in the human lung: a proteomic approach. Am J Respir Cell Mol Biol. 2008;38(5):541–50.PubMedCrossRefGoogle Scholar
  110. 110.
    Poppek D, Grune T. Proteasomal defense of oxidative protein modifications. Antioxid Redox Signal. 2006;8(1–2):173–84.PubMedCrossRefGoogle Scholar
  111. 111.
    Osorio F, Lambrecht B, Janssens S. The UPR and lung disease. Semin Immunopathol. 2013;35(3):293–306.PubMedCrossRefGoogle Scholar
  112. 112.
    Wei J, Rahman S, Ayaub EA, Dickhout JG, Ask K. Protein misfolding and endoplasmic reticulum stress in chronic lung disease. Chest. 2013;143(4):1098–105.PubMedCrossRefGoogle Scholar
  113. 113.
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–40.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, et al. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010;59(8):1899–905.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Zode GS, Kuehn MH, Nishimura DY, Searby CC, Mohan K, Grozdanic SD, et al. Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. J Clin Invest. 2011;121(9):3542–53.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Sorrentino SA, Besler C, Rohrer L, Meyer M, Heinrich K, Bahlmann FH, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. 2010;121(1):110–22.PubMedCrossRefGoogle Scholar
  117. 117.
    Mily A, Rekha RS, Kamal SM, Akhtar E, Sarker P, Rahim Z, et al. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis. BMC Pulm Med. 2013;13:23.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Klein S. Washington University School of Medicine. Effect of endoplasmic reticulum stress on metabolic function (TUDCA/PBA). 1999. http://clinicaltrials.gov/show/NCT00004451. Updated 29 Nov 2005; Accessed 6 May 2017.
  119. 119.
    Rubenstein R. The Children’s Hospital of Philadelphia. Phenylbutyrate/genistein duotherapy in delta F508-heterozygotes (for cystic fibrosis). 1999. http://clinicaltrials.gov/show/NCT000164744. Updated 23 Jun 2005; Accessed 6 May 2017.
  120. 120.
    Makhija L, Krishnan V, Rehman R, Chakraborty S, Maity S, Mabalirajan U, et al. Chemical chaperones mitigate experimental asthma by attenuating endoplasmic reticulum stress. Am J Respir Cell Mol Biol. 2014;50(5):923–31.PubMedCrossRefGoogle Scholar
  121. 121.
    MacGlashan DW, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, et al. Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol. 1997;158(3):1438–45.PubMedGoogle Scholar
  122. 122.
    Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C, et al. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459–65.PubMedCrossRefGoogle Scholar
  123. 123.
    Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170(6):583–93.PubMedCrossRefGoogle Scholar
  124. 124.
    Chipps BE, Lanier B, Milgrom H, Deschildre A, Hedlin G, Szefler SJ, et al. Omalizumab in children with uncontrolled allergic asthma: review of clinical trial and real-world experience. J Allergy Clin Immunol. 2017;139(5):1431–44.PubMedCrossRefGoogle Scholar
  125. 125.
    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.PubMedCrossRefGoogle Scholar
  126. 126.
    Agrawal DK, Shao Z. Pathogenesis of allergic airway inflammation. Curr Allergy Asthma Rep. 2010;10:39–48.Google Scholar
  127. 127.
    Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2(5):525–36.e1.PubMedCrossRefGoogle Scholar
  128. 128.
    Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 1997;155(6):1828–34.PubMedCrossRefGoogle Scholar
  129. 129.
    Samitas K, Delimpoura V, Zervas E, Gaga M. Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives. Eur Respir Rev. 2015;24(138):594–601.PubMedCrossRefGoogle Scholar
  130. 130.
    Teach SJ, Gill MA, Togias A, Sorkness CA, Arbes SJ Jr, Calatroni A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476–85.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genome wide association study of asthma. N Engl J Med. 2010;363(13):1211–21.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    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
  133. 133.
    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.PubMedCrossRefGoogle Scholar
  134. 134.
    Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2011;139(1):28–35.PubMedCrossRefGoogle Scholar
  135. 135.
    US Food and Drug Administration (FDA). Xolair (omalizumab) US prescribing information. 2014. www.accessdata.fda.gov/drugsatfda_docs/label/2014/103976s5161lbl.pdf. Accessed 23 Nov 2016.
  136. 136.
    European Medicines Agency (EMA). Xolair (omalizumab) summary of product characteristics. 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000606/WC500057298.pdf. Accessed 23 Nov 2016.
  137. 137.
    National Institute for Health and Care Excellence (NICE). Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11. 2010. https://www.nice.org.uk/guidance/ta201. Accessed 23 Nov 2016.
  138. 138.
    National Institute for Health and Care Excellence (NICE). Omalizumab for treating severe persistent allergic asthma (technology appraisal guidance). 2013. www.nice.org.uk/guidance/ta278. Accessed 31 May 2016.
  139. 139.
    Papadopoulos NG, Arakawa H, Carlsen KH, Custovic A, Gern J, Lemanske R, et al. International consensus on (ICON) pediatric asthma. Allergy. 2012;67(8):976–97.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    National Asthma Education and Prevention Program. Third Expert Panel on the Diagnosis and Management of Asthma. Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007.Google Scholar
  141. 141.
    Arm JP, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy. 2014;44(11):1371–85.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Maes T, Joos GF, Brusselle GG. Targeting interleukin-4 in asthma: lost in translation? Am J Respir Cell Mol Biol. 2012;47(3):261–70.PubMedCrossRefGoogle Scholar
  143. 143.
    Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282(5397):2261–3.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: central mediator of allergic asthma. Science. 1998;282(5397):2258–61.PubMedCrossRefGoogle Scholar
  145. 145.
    Chatila TA. Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med. 2004;10(10):493–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an nterleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370(9596):1422–31.PubMedCrossRefGoogle Scholar
  147. 147.
    Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP, Wenzel SE, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor a antagonist. J Allergy Clin Immunol. 2012;130(2):516–22.e4.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Corren J, Busse W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, et al. A randomized, controlled, phase 2 study of AMG 317, an IL- 4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med. 2010;181(8):788–96.PubMedCrossRefGoogle Scholar
  149. 149.
    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.PubMedCrossRefGoogle Scholar
  150. 150.
    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 β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31–44.PubMedCrossRefGoogle Scholar
  151. 151.
    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.PubMedCrossRefGoogle Scholar
  152. 152.
    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.PubMedCrossRefGoogle Scholar
  153. 153.
    DeBoever EH, Ashman C, Cahn AP, Locantore NW, Overend P, Pouliquen IJ, et al. Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. J Allergy Clin Immunol. 2014;133(4):989–96.CrossRefGoogle Scholar
  154. 154.
    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.PubMedCrossRefGoogle Scholar
  155. 155.
    Brightling CE, Chanez P, Leigh R, O'Byrne PM, Korn S, She D, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692–701.PubMedCrossRefGoogle Scholar
  156. 156.
    Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood. 1989;73(6):1504–12.PubMedGoogle Scholar
  157. 157.
    Licona-Limon P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol. 2013;14(6):536–42.PubMedCrossRefGoogle Scholar
  158. 158.
    Holtzman MJ, Byers DE, Alexander-Brett J, Wang X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol. 2014;14(10):686–98.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Bernink JH, Germar K, Spits H. The role of ILC2 in pathology of type 2 inflammatory diseases. Curr Opin Immunol. 2014;31:115–20.PubMedCrossRefGoogle Scholar
  160. 160.
    Russell R, Brightling CE. Anti-IL-5 for severe asthma: aiming high to achieve success. Chest. 2016;150(4):766–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71.PubMedCrossRefGoogle Scholar
  162. 162.
    Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356(9248):2144–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.PubMedCrossRefGoogle Scholar
  164. 164.
    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
  165. 165.
    Nair P, Pizzichini MM, Kjarsgaard M, Kjarsgaard M, Inman MD, Efthimiadis A, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93.PubMedCrossRefGoogle Scholar
  166. 166.
    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.PubMedCrossRefGoogle Scholar
  167. 167.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing eff ect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.PubMedCrossRefGoogle Scholar
  168. 168.
    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
  169. 169.
    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
  170. 170.
    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.PubMedCrossRefGoogle Scholar
  171. 171.
    FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–41.PubMedCrossRefGoogle Scholar
  172. 172.
    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 β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.PubMedCrossRefGoogle Scholar
  173. 173.
    Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomized dose-ranging study. Lancet Respir Med. 2014;2(11):879–90.PubMedCrossRefGoogle Scholar
  174. 174.
    Toba K, Koike T, Shibata A, Hashimoto S, Takahashi M, Masuko M, et al. Novel technique for the direct flow cytofluorometric analysis of human basophils in unseparated blood and bone marrow, and the characterization of phenotype and peroxidase of human basophils. Cytometry. 1999;35(3):249–59.PubMedCrossRefGoogle Scholar
  175. 175.
    Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132(5):1086–96.e5.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Liu YJ, Soumelis V, Watanabe N, Ito T, Wang YH, Malefyt Rde W, et al. TSLP: an epithelial cell cytokine that regulates T cell diff erentiation by conditioning dendritic cell maturation. Annu Rev Immunol. 2007;25:193–219.PubMedCrossRefGoogle Scholar
  177. 177.
    Ying S, O’Connor B, Ratoff J, Meng Q, Fang C, Cousins D, et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 2008;181(4):2790–8.PubMedCrossRefGoogle Scholar
  178. 178.
    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.PubMedCrossRefGoogle Scholar
  179. 179.
    MedImmune LLC. A phase 2 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MEDI9929 in adult subjects with inadequately controlled, severe asthma. 2013. http://clinicaltrials.gov/show/NCT02054130. Updated 13 Apr 2017; Accessed 6 May 2017.
  180. 180.
    Porsbjerg C. Effects of anti-TSLP on airway hyperresponsiveness and mast cell phenotype in asthma—a randomized double-blind, placebo-controlled trial of MEDI9929. 2016. http://clinicaltrials.gov/show/NCT02698501. Updated 3 Jan 2017; Accessed 6 May 2017.
  181. 181.
    Robinson DS, Campbell DA, Barnes PJ. Addition of an anti-leukotriene to therapy in chronic severe asthma in a clinic setting: a double-blind, randomised, placebo-controlled study. Lancet. 2001;357(9273):2007–11.PubMedCrossRefGoogle Scholar
  182. 182.
    Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med. 1998;339(3):147–52.PubMedCrossRefGoogle Scholar
  183. 183.
    Ohnishi H, Miyahara N, Gelfand EW. The role of leukotriene B(4) in allergic diseases. Allergol Int. 2008;57(4):291–8.PubMedCrossRefGoogle Scholar
  184. 184.
    Tager AM, Luster AD. BLT1 and BLT2: the leukotriene B(4) receptors. Prostaglandins Leukot Essent Fatty Acids. 2003;69(2–3):123–34.PubMedCrossRefGoogle Scholar
  185. 185.
    Rao NL, Riley JP, Banie H, Xue X, Sun B, Crawford S, et al. Leukotriene A(4) hydrolase inhibition attenuates allergic airway inflammation and hyperresponsiveness. Am J Respir Crit Care Med. 2010;181(9):899–907.PubMedCrossRefGoogle Scholar
  186. 186.
    Cho KJ, Seo JM, Shin Y, Yoo MH, Park CS, Lee SH, et al. Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor. Am J Respir Cell Mol Biol. 2010;42(3):294–303.PubMedCrossRefGoogle Scholar
  187. 187.
    Aronson JK. Side effects of drugs annual: a worldwide yearly survey of new data and trends in adverse drug reactions and interactions. Side Effects Drugs Annu. 2010;32:1–1004.CrossRefGoogle Scholar
  188. 188.
    Grant GE, Rokach J, Powell WS. 5-Oxo-ETE and the OXE receptor. Prostaglandins Other Lipid Mediat. 2009;89(3–4):98–104.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Kent SE, Boyce M, Diamant Z, Singh D, O’Connor BJ, Saggu PS, et al. The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma. Clin Exp Allergy. 2013;43(2):177–86.PubMedCrossRefGoogle Scholar
  190. 190.
    Pettipher R, Hansel TT, Armer R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 2007;6(4):313–25.PubMedCrossRefGoogle Scholar
  191. 191.
    Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388–94.PubMedCrossRefGoogle Scholar
  192. 192.
    Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E, Busse WW, et al. Mast cell phenotype, location, and activation in severe asthma: data from the severe asthma research program. Am J Respir Crit Care Med. 2011;183(3):299–309.PubMedCrossRefGoogle Scholar
  193. 193.
    Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015;386(9998):1086–96.PubMedCrossRefGoogle Scholar
  194. 194.
    Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy. 2012;42(1):38–48.PubMedCrossRefGoogle Scholar
  195. 195.
    Busse WW, Wenzel SE, Meltzer EO, Kerwin EM, Liu MC, Zhang N, et al. Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients. Allergy Clin Immunol. 2013;131(2):339–45.CrossRefGoogle Scholar
  196. 196.
    Hall IP, Fowler AV, Gupta A, Tetzlaff K, Nivens MC, Sarno M, et al. Effi cacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther. 2015;32:37–44.PubMedCrossRefGoogle Scholar
  197. 197.
    Berair R, Gonem S, Singapuri A, Hartley R, Laurencin M, Bacher G, et al. Effect of QAW039, an oral prostaglandin D2 receptor (DP2/CrTh2) antagonist upon sputum and bronchial eosinophilic inflammation and clinical outcomes in treatment-resistant asthma: a phase 2a randomised placebo-controlled trial. Am J Respir Crit Care Med. 2015;191:A6361.Google Scholar
  198. 198.
    Lodowski DT, Palczewski K. Chemokine receptors and other G protein coupled receptors. Curr Opin HIV AIDS. 2009;4(2):88–95.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Gauvreau GM, Boulet LP, Cockcroft DW, Baatjes A, Cote J, Deschesnes F, et al. Antisense therapy against CCR3 and the common beta chain attenuates allergen induced eosinophilic responses. Am J Respir Crit Care Med. 2008;177(9):952–8.PubMedCrossRefGoogle Scholar
  200. 200.
    Tomankova T, Kriegova E, Liu M. Chemokine receptors and their therapeutic opportunities in diseased lung: far beyond leukocyte trafficking. Am J Physiol Lung Cell Mol Physiol. 2015;308(7):L603–18.PubMedCrossRefGoogle Scholar
  201. 201.
    Antoniu SA. Mogamulizumab, a humanized mAb against C-C chemokine receptor 4 for the potential treatment of T-cell lymphomas and asthma. Curr Opin Mol Ther. 2010;12(6):770–9.PubMedGoogle Scholar
  202. 202.
    Solari R, Pease JE. Targeting chemokine receptors in disease—a case study of CCR4. Eur J Pharmacol. 2015;763(Pt B):169–77.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Cahn A, Hodgson S, Wilson R, Robertson J, Watson J, Beerahee M, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013;14:14.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Kips JC, Tavernier J, Pauwels RA. Tumor necrosis factor causes bronchial hyperresponsiveness in rats. Am Rev Respir Dis. 1992;145(2 Pt 1):33236.Google Scholar
  205. 205.
    Holgate ST, Noonan M, Chanez P, Busse W, Dupont L, Pavord I, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011;37(6):1352–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Proudfoot AE, Power CA, Schwarz MK. Anti-chemokine small molecule drugs: a promising future? Expert Opin Investig Drugs. 2010;19(3):345–55.PubMedCrossRefGoogle Scholar
  207. 207.
    Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med. 2006;174(7):753–62.PubMedCrossRefGoogle Scholar
  208. 208.
    Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlén SE, 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):549–58.PubMedCrossRefGoogle Scholar
  209. 209.
    Park SJ, Lee KS, Kim SR, Min KH, Choe YH, Moon H, et al. Peroxisome proliferator-activated receptor gamma agonist down-regulates IL-17 expression in a murine model of allergic airway inflammation. J Immunol. 2009;183(5):3259–67.PubMedCrossRefGoogle Scholar
  210. 210.
    Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Pagé N, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001;108(3):430–8.PubMedCrossRefGoogle Scholar
  211. 211.
    Barczyk A, Pierzchala W, Sozañska E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir Med. 2003;97(6):726–33.PubMedCrossRefGoogle Scholar
  212. 212.
    Sun Y-C, Zhou Q-T, Yao W-Z. Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma. Chin Med J. 2005;118(11):953–6.PubMedGoogle Scholar
  213. 213.
    Bullens DM, Truyen E, Coteur L, Dilissen E, Hellings PW, Dupont LJ, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res. 2006;7:135.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA, et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol. 2008;181(6):4299–310.PubMedCrossRefGoogle Scholar
  215. 215.
    Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, 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):1294–302.PubMedCrossRefGoogle Scholar
  216. 216.
    Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y, et al. NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy. 2011;66(8):1047–57.PubMedCrossRefGoogle Scholar
  217. 217.
    Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol. 2008;181(6):3755–9.PubMedCrossRefGoogle Scholar
  218. 218.
    Gregory LG, Lloyd CM. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 2011;32(9):402–11.PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Kim RY, Pinkerton JW, Essilfie AT, Robertson AA, Baines KJ, Brown AC, et al. Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med 2017. doi:10.1164/rccm.201609-1830OC.Google Scholar
  220. 220.
    Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017;49(2):pii: 1602135.CrossRefGoogle Scholar
  221. 221.
    Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur Respir J. 2010;35(3):564–70.PubMedCrossRefGoogle Scholar
  222. 222.
    Nair P, Gaga M, Zervas E, Alagha K, Hargreave FE, O'Byrne PM, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42(7):097–1103.CrossRefGoogle Scholar
  223. 223.
    de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol. 2016;16(6):378–91.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Moss RB. Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis. Eur Respir J. 2014;43(5):1487–500.PubMedCrossRefGoogle Scholar
  225. 225.
    Denning DW, Van Wye JE, Lewiston NJ, Stevens DA. Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole. Chest. 1991;100(3):813–9.PubMedCrossRefGoogle Scholar
  226. 226.
    Pacheco A, Martin JA, Cuevas M. Serologic response to itraconazole in allergic bronchopulmonary aspergillosis. Chest. 1993;103(3):980–1.PubMedCrossRefGoogle Scholar
  227. 227.
    Germaud P, Tuchais E. Allergic bronchopulmonary aspergillosis treated with itraconazole. Chest. 1995;107(3):883.PubMedCrossRefGoogle Scholar
  228. 228.
    Salez F, Brichet A, Desurmont S, Grosbois JM, Wallaert B, Tonnel AB, et al. Effects of itraconazole therapy in allergic bronchopulmonary aspergillosis. Chest. 1999;116(6):1658–65.CrossRefGoogle Scholar
  229. 229.
    Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342(11):756–62.PubMedCrossRefGoogle Scholar
  230. 230.
    Wark PA, Hensley MJ, Saltos N, Boyle MJ, Toneguzzi RC, Epid GD, et al. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol. 2003;111(5):952–7.PubMedCrossRefGoogle Scholar
  231. 231.
    Wark P. Pathogenesis of allergic bronchopulmonary aspergillosis and an evidence-based review of azoles in treatment. Respir Med. 2004;98(10):915–23.PubMedCrossRefGoogle Scholar
  232. 232.
    Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev. 2004;3:CD001108.Google Scholar
  233. 233.
    Denning DW, O’Driscoll BR, Powell G, Chew F, Atherton GT, Vyas A, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: the Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med. 2009;179(1):11–8.PubMedCrossRefGoogle Scholar
  234. 234.
    Vicencio AG, Chupp GL, Tsirilakis K, He X, Kessel A, Nandalike K, et al. CHIT1 mutations: genetic risk factor for severe asthma with fungal sensitization? Pediatrics. 2010;126(4):e982–5.PubMedCrossRefGoogle Scholar
  235. 235.
    Vicencio AG, Muzumdar H, Tsirilakis K, Kessel A, Nandalike K, Goldman DL, et al. Severe asthma with fungal sensitization in a child: response to itraconazole therapy. Pediatrics. 2010;125(5):e1255–8.PubMedCrossRefGoogle Scholar
  236. 236.
    Proesmans M, Vermeulen F, Vreys M, De Boeck K. Use of nebulized amphotericin B in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis. Int J Pediatr. 2010;2010:376287.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Hayes D Jr, Murphy BS, Lynch JE, Feola DJ. Aerosolized amphotericin for the treatment of allergic bronchopulmonary aspergillosis. Pediatr Pulmonol. 2010;45(11):1145–8.PubMedCrossRefGoogle Scholar
  238. 238.
    Metz G, Kraft M. Effects of atypical infections with mycoplasma and chlamydia on asthma. Immunol Allergy Clin N Am. 2010;30(4):575–85.CrossRefGoogle Scholar
  239. 239.
    Kraft M, Torvik JA, Trudeau JB, Wenzel SE, Martin RJ. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol. 1996 Jun;97(6):1242–6.PubMedCrossRefGoogle Scholar
  240. 240.
    Sutherland ER, King TS, Icitovic N, Ameredes BT, Bleecker E, Boushey HA, et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J Allergy Clin Immunol. 2010;126(4):747–53.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251–9.PubMedCrossRefGoogle Scholar
  242. 242.
    Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322–9.PubMedCrossRefGoogle Scholar
  243. 243.
    Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta-analysis. Allergy. 2013;68(5):569–79.PubMedCrossRefGoogle Scholar
  244. 244.
    Johnston SL, Pattemore PK, Sanderson G, Smith S, Campbell MJ, Josephs LK, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med. 1996;154(3 Pt 1):654–60.PubMedCrossRefGoogle Scholar
  245. 245.
    Corne JM, Marshall C, Smith S, Schreiber J, Sanderson G, Holgate ST, et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet. 2002;359(9309):831–4.PubMedCrossRefGoogle Scholar
  246. 246.
    Papadopoulos NG, Christodoulou I, Rohde G, Agache I, Almqvist C, Bruno A, et al. Viruses and bacteria in acute asthma exacerbations—a GA2 LEN-DARE systematic review. Allergy. 2011;66(4):458–68.PubMedCrossRefGoogle Scholar
  247. 247.
    Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol. 2010;125(6):1178–87.PubMedCrossRefGoogle Scholar
  248. 248.
    Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31(1):143–78.PubMedCrossRefGoogle Scholar
  249. 249.
    Calışkan M, Bochkov YA, Kreiner-Møller E, Bønnelykke K, Stein MM, Du G, Bisgaard H, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med. 2013;368(15):1398–407.PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201(6):937–47.PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Djukanović R, Harrison T, Johnston SL, Gabbay F, Wark P, Thomson NC, et al. The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial. Am J Respir Crit Care Med. 2014;190(2):145–54.PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Holgate ST. Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches? J Allergy Clin Immunol. 2011;128(3):495–505.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Respiratory Medicine and Allergy, Department of Internal MedicineChonbuk National University Medical SchoolJeonjuSouth Korea

Personalised recommendations