Pediatric Drugs

, Volume 15, Issue 4, pp 291–302 | Cite as

Newer Treatments in the Management of Pediatric Asthma

Review Article

Abstract

Asthma control remains a significant challenge in the pediatric age range in which ongoing loss of lung function in children with persistent asthma has been reported, despite the use of regular preventer therapy. This has important implications for observed mortality and morbidity during adulthood. Over the past decade, there has been an emergence of other treatment adjuncts, such as anti-Immunoglobulin E (IgE)-directed therapy, low dose theophylline, and the use of macrolide antibiotics, yet their exact role in asthma management remains unclear, despite omalizumab now being incorporated into several international asthma guidelines. As with many aspects of pediatric care, this is driven by a lack of appropriately designed pediatric trials. Extrapolation of data reported in adult studies may be appropriate for adolescent asthma, but is not for younger age groups, in which important pathophysiological differences exist. Novel drugs under development offer potential for benefit in the future, but to date existing data are in most cases limited to adults. Pediatric asthma also offers unique potential to prevent or modify the underlying pathophysiology. Although attempts to do so have been unsuccessful to date, advances may yet come from this approach, as our understanding about the interaction between genetics, environmental factors, and viral illness improve. This review provides an overview of the newer treatment options available for management of pediatric asthma and discusses the merits of other novel therapies in development, as we search to optimize management and improve future outcomes.

References

  1. 1.
    Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, Chipps BE, et al. Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol. 2009;124(5):895–902.e1–4.Google Scholar
  2. 2.
    Fitzpatrick AM, Teague WG. Progressive airflow limitation is a feature of children with severe asthma. J Allergy Clin Immunol. 2011;127(1):282–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Covar RA, Spahn JD, Murphy JR, Szefler SJ. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004;170(3):234–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol. 2006;118(5):1040–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Narayanan M, Owers-Bradley J, Beardsmore CS, Mada M, Ball I, Garipov R, et al. Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance. Am J Respir Crit Care Med. 2012;185(2):186–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clinical Immunol. 2007;119(2):405–13.CrossRefGoogle Scholar
  7. 7.
    Barnes PJ. New therapies for asthma: is there any progress? Trends Pharmacol Sci. 2010;31(7):335–43.PubMedCrossRefGoogle Scholar
  8. 8.
    Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012;129(1):48–59.PubMedCrossRefGoogle Scholar
  9. 9.
    Bush A, Pedersen S, Hedlin G, Baraldi E, Barbato A, de Benedictis F, et al. Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where? Eur Respir J Official J Eur Soc Clin Respir Physiol. 2011;38(4):947–58.Google Scholar
  10. 10.
    Sly PD, Jones CM. New and future developments of therapy for asthma in children. Eur Respir Monogr. 2012;56:224–34.CrossRefGoogle Scholar
  11. 11.
    Szefler SJ. Advances in pediatric asthma in 2010: addressing the major issues. J Allergy Clin Immunol. 2011;127(1):102–15.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3):133–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol. 2006;118(1):53–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Toelle BG, Ng KK, Crisafulli D, Belousova EG, Almqvist C, Webb K, et al. Eight-year outcomes of the Childhood Asthma Prevention Study. J Allergy Clin Immunol. 2010;126(2):388–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–97.PubMedCrossRefGoogle Scholar
  17. 17.
    Just J, Gouvis-Echraghi R, Rouve S, Wanin S, Moreau D, Annesi-Maesano I. Two novel, severe asthma phenotypes identified during childhood using a clustering approach. Eur Respir J Official J Eur Soc Clin Respir Physiol. 2012;40(1):55–60.CrossRefGoogle Scholar
  18. 18.
    Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med. 1996;154(5):1505–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, et al. Inflammation of small airways in asthma. J Allergy Clin Immunol. 1997;100(1):44–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Berry M, Hargadon B, Morgan A, Shelley M, Richter J, Shaw D, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J. 2005;25(6):986–91.PubMedCrossRefGoogle Scholar
  21. 21.
    Verbanck S, Schuermans D, Paiva M, Vincken W. The functional benefit of anti-inflammatory aerosols in the lung periphery. J Allergy Clin Immunol. 2006;118(2):340–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Macleod KA, Horsley AR, Bell NJ, Greening AP, Innes JA, Cunningham S. Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease. Thorax. 2009;64(1):33–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Sonnappa S, Bastardo CM, Wade A, Saglani S, McKenzie SA, Bush A, et al. Symptom-pattern phenotype and pulmonary function in preschool wheezers. J Allergy Clin Immunol. 2010;126(3):519–26.PubMedCrossRefGoogle Scholar
  24. 24.
    Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005;60(3):302–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Holgate ST, Chuchalin AG, Hebert J, Lotvall J, Persson GB, Chung KF, et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy. 2004;34(4):632–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Thoracic Society of Australia and New Zealand. Omalizumab: Recommendations for use in the Australasian context. 2009. http://www.thoracic.org.au.
  27. 27.
    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. Annals Intern Med. 2011;154(9):573–82.CrossRefGoogle Scholar
  28. 28.
    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
  29. 29.
    Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108(2):E36.PubMedCrossRefGoogle Scholar
  30. 30.
    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. New Engl J Med. 2011;364(11):1005–15.PubMedCrossRefGoogle Scholar
  31. 31.
    Kulus M, Hebert J, Garcia E, Fowler Taylor A, Fernandez Vidaurre C, Blogg M. Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma. Curr Med Res Opin. 2010;26(6):1285–93.Google Scholar
  32. 32.
    Lemanske RF Jr, Nayak A, McAlary M, Everhard F, Fowler-Taylor A, Gupta N. Omalizumab improves asthma-related quality of life in children with allergic asthma. Pediatrics. 2002;110(5):e55.PubMedCrossRefGoogle Scholar
  33. 33.
    Brodlie M, McKean MC, Moss S, Spencer DA. The oral corticosteroid-sparing effect of omalizumab in children with severe asthma. Arch Dis Child. 2012;97(7):604–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Pavord ID, Bush A. Anti-IgE for asthma in inner-city children. New Engl J Med. 2011;364(26):2556–7 (author reply 7–8).Google Scholar
  35. 35.
    Berger W, Gupta N, McAlary M, Fowler-Taylor A. Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol. 2003;91(2):182–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Limb SL, Starke PR, Lee CE, Chowdhury BA. Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma. J Allergy Clin Immunol. 2007;120(6):1378–81.PubMedCrossRefGoogle Scholar
  37. 37.
    Takhar P, Corrigan CJ, Smurthwaite L, O’Connor BJ, Durham SR, Lee TH, et al. Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J Allergy Clin Immunol. 2007;119(1):213–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Burch J, Griffin S, McKenna C, Walker S, Paton J, Wright K, et al. Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years: a NICE single technology appraisal. Pharmacoeconomics. 2012;30(11):991–1104.Google Scholar
  39. 39.
    Oba Y, Salzman GA. Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. J Allergy Clin Immunol. 2004;114(2):265–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Bush A, Pavord I. Omalizumab: NICE to USE you, to LOSE you NICE. Thorax. 2013;68:5–6.CrossRefGoogle Scholar
  41. 41.
    Robinson PD, Van Asperen P. Asthma in childhood. Pediatr Clin North Am. 2009;56(1):191–226, xii.Google Scholar
  42. 42.
    Friedman HS, Navaratnam P, McLaughlin J. Adherence and asthma control with mometasone furoate versus fluticasone propionate in adolescents and young adults with mild asthma. J Asthma. 2010;47(9):994–1000.PubMedGoogle Scholar
  43. 43.
    Milgrom H. Mometasone furoate in children with mild to moderate persistent asthma: a review of the evidence. Paediatr Drugs. 2010;12(4):213–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Skoner DP, Meltzer EO, Milgrom H, Stryszak P, Teper A, Staudinger H. Effects of inhaled mometasone furoate on growth velocity and adrenal function: a placebo-controlled trial in children 4–9 years old with mild persistent asthma. J Asthma. 2011;48(8):848–59.PubMedCrossRefGoogle Scholar
  45. 45.
    Gelfand EW, Georgitis JW, Noonan M, Ruff ME. Once-daily ciclesonide in children: efficacy and safety in asthma. J Pediatr. 2006;148(3):377–83.PubMedCrossRefGoogle Scholar
  46. 46.
    Pedersen S, Garcia Garcia ML, Manjra A, Theron I, Engelstatter R. A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma. Pediatr Pulmonol. 2006;41(10):954–61.Google Scholar
  47. 47.
    Skoner DP, Maspero J, Banerji D. Assessment of the long-term safety of inhaled ciclesonide on growth in children with asthma. Pediatrics. 2008;121(1):e1–14.PubMedCrossRefGoogle Scholar
  48. 48.
    Korn S, Buhl R. Efficacy of a fixed combination of ciclesonide and formoterol: the EXCITED-study. Respir Med. 2012;106(1):57–67.PubMedCrossRefGoogle Scholar
  49. 49.
    Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012;64(3):450–504.PubMedCrossRefGoogle Scholar
  50. 50.
    Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163(1):29–43.PubMedCrossRefGoogle Scholar
  51. 51.
    Seddon P, Bara A, Ducharme FM, Lasserson TJ. Oral xanthines as maintenance treatment for asthma in children. Cochrane Database Syst Rev. 2006(1):CD002885.Google Scholar
  52. 52.
    Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med. 2004;170(2):141–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Derks MG, Koopmans RP, Oosterhoff E, Van Boxtel CJ. Prevention by theophylline of beta-2-receptor down regulation in healthy subjects. Eur J Drug Metab Pharmacokinet. 2000;25(3–4):179–88.Google Scholar
  54. 54.
    Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Nakazawa T, et al. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol. 2000;67(4):529–35.PubMedGoogle Scholar
  55. 55.
    Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004;200(5):689–95.PubMedCrossRefGoogle Scholar
  56. 56.
    Suessmuth S, Freihorst J, Gappa M. Low-dose theophylline in childhood asthma: a placebo-controlled, double-blind study. Pediatr Allergy Immunol. 2003;14(5):394–400.PubMedCrossRefGoogle Scholar
  57. 57.
    Kondo N, Katsunuma T, Odajima Y, Morikawa A. A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children. Allergol Int. 2006;55(3):287–93.PubMedCrossRefGoogle Scholar
  58. 58.
    Sankar J, Lodha R, Kabra SK. Doxofylline: The next generation methylxanthine. Indian J Pediatr. 2008;75(3):251–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Good JT Jr, Rollins DR, Martin RJ. Macrolides in the treatment of asthma. Curr Opin Pulm Med. 2012;18(1):76–84.PubMedCrossRefGoogle Scholar
  60. 60.
    Kudoh S. Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med. 1998;4(2):116–21.PubMedCrossRefGoogle Scholar
  61. 61.
    Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749–56.PubMedCrossRefGoogle Scholar
  63. 63.
    Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978–84.PubMedCrossRefGoogle Scholar
  64. 64.
    Clement A, Tamalet A, Leroux E, Ravilly S, Fauroux B, Jais JP. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax. 2006;61(10):895–902.PubMedCrossRefGoogle Scholar
  65. 65.
    Fleet JE, Guha K, Piper S, Banya W, Bilton D, Hodson ME. A retrospective analysis of the impact of azithromycin maintenance therapy on adults attending a UK cystic fibrosis clinic. J Cyst Fibrosis. 2013;12(1):49–53.Google Scholar
  66. 66.
    Kamada AK, Hill MR, Ikle DN, Brenner AM, Szefler SJ. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol. 1993;91(4):873–82.PubMedCrossRefGoogle Scholar
  67. 67.
    Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148–55.PubMedCrossRefGoogle Scholar
  68. 68.
    Piacentini GL, Peroni DG, Bodini A, Pigozzi R, Costella S, Loiacono A, et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc. 2007;28(2):194–8.Google Scholar
  69. 69.
    Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol. 1991;10(3):178–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Ball BD, Hill MR, Brenner M, Sanks R, Szefler SJ. Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy. 1990;65(1):37–45.PubMedGoogle Scholar
  71. 71.
    Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol. 1999;103(6):1031–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Varis T, Kivisto KT, Backman JT, Neuvonen PJ. Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol. 1999;85(1):29–32.PubMedCrossRefGoogle Scholar
  73. 73.
    Ekici A, Ekici M, Erdemoglu AK. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma. 2002;39(2):181–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Fonseca-Aten M, Okada PJ, Bowlware KL, Chavez-Bueno S, Mejias A, Rios AM, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;97(4):457–63.PubMedCrossRefGoogle Scholar
  75. 75.
    Koutsoubari I, Papaevangelou V, Konstantinou GN, Makrinioti H, Xepapadaki P, Kafetzis D, et al. Effect of clarithromycin on acute asthma exacerbations in children: an open randomized study. Pediatr Allergy Immunol. 2012;23(4):385–90.PubMedCrossRefGoogle Scholar
  76. 76.
    Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121(6):1782–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Chu HW, Kraft M, Rex MD, Martin RJ. Evaluation of blood vessels and edema in the airways of asthma patients: regulation with clarithromycin treatment. Chest. 2001;120(2):416–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011;127(2):372–81.e1–3.Google Scholar
  79. 79.
    Pires dos Santos R, Kuchenbecker R. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 Aug 23;367(8):774-5; author reply 5.Google Scholar
  80. 80.
    Hansbro PM, Kaiko GE, Foster PS. Cytokine/anti-cytokine therapy—novel treatments for asthma? Br J Pharmacol. 2011;163(1):81–95.Google Scholar
  81. 81.
    Alcorn JF, Crowe CR, Kolls JK. TH17 cells in asthma and COPD. Annu Rev Physiol. 2010;72:495–516.PubMedCrossRefGoogle Scholar
  82. 82.
    Wills-Karp M, Finkelman FD. Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal. 2008;1(51):pe55.Google Scholar
  83. 83.
    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
  84. 84.
    Kraft M. Asthma phenotypes and interleukin-13–moving closer to personalized medicine. N Engl J Med. 2011;365(12):1141–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA. 2010;107(32):14170–5.CrossRefPubMedGoogle Scholar
  86. 86.
    Zeskind B. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(25):2432; author reply 3–4.Google Scholar
  87. 87.
    Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-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
  88. 88.
    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 alpha antagonist. J Allergy Clin Immunol. 2012;130(2):516–22.e4.Google Scholar
  89. 89.
    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.PubMedCrossRefGoogle Scholar
  90. 90.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93.PubMedCrossRefGoogle Scholar
  91. 91.
    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
  92. 92.
    Wu AC, Tantisira K, Li L, Fuhlbrigge AL, Weiss ST, Litonjua A. Effect of Vitamin D and inhaled corticosteroid treatment on lung function in children. Am J Respir Crit Care Med. 2012;186(6):508–13.PubMedCrossRefGoogle Scholar
  93. 93.
    Kreindler JL. Is the best offense a good D-fense?: Should we use Vitamin D as adjunctive therapy for asthma? Am J Respir Crit Care Med. 2012;186(6):470–2.PubMedCrossRefGoogle Scholar
  94. 94.
    Gupta A, Sjoukes A, Richards D, Banya W, Hawrylowicz C, Bush A, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184(12):1342–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965–74.PubMedCrossRefGoogle Scholar
  96. 96.
    Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado Y, Panettieri R Jr, et al. Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol. 2008;155(1):84–92.PubMedCrossRefGoogle Scholar
  97. 97.
    Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006;116(1):146–55.PubMedCrossRefGoogle Scholar
  98. 98.
    Bilinski KL, Boyages SC. The rising cost of vitamin D testing in Australia: time to establish guidelines for testing. Med J Aust. 2012;197(2):90.PubMedCrossRefGoogle Scholar
  99. 99.
    Shee C. Is hypovitaminosis D a consequence rather than cause of disease? Thorax. 2013 [Epub ahead of print].Google Scholar
  100. 100.
    Sawicki GS, Strunk RC, Schuemann B, Annett R, Weiss S, Fuhlbrigge AL. Patterns of inhaled corticosteroid use and asthma control in the Childhood Asthma Management Program Continuation Study. Annals Allergy Asthma Immunol Official Publ Am Coll Allergy Asthma Immunol. 2010;104(1):30–5.CrossRefGoogle Scholar
  101. 101.
    Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol. 1996;98(6 Pt 1):1051–7.PubMedCrossRefGoogle Scholar
  102. 102.
    Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2009;180(9):817–22.PubMedCrossRefGoogle Scholar
  103. 103.
    ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med. 2004;170(6):601–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Bauman LJ, Wright E, Leickly FE, Crain E, Kruszon-Moran D, Wade SL, et al. Relationship of adherence to pediatric asthma morbidity among inner-city children. Pediatrics. 2002;110(1 Pt 1):e6.PubMedCrossRefGoogle Scholar
  105. 105.
    Bender BG. Overcoming barriers to nonadherence in asthma treatment. J Allergy Clin Immunol. 2002;109(6 Suppl):S554–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Wieshammer S, Dreyhaupt J. Dry powder inhalers: which factors determine the frequency of handling errors? Respiration. 2008;75(1):18–25.PubMedCrossRefGoogle Scholar
  107. 107.
    Grover C, Armour C, Van Asperen PP, Moles R, Saini B. Medication use in children with asthma: not a child size problem. J Asthma. 2011;48(10):1085–103.PubMedCrossRefGoogle Scholar
  108. 108.
    Jackson DJ, Johnston SL. The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol. 2010;125(6):1178–87; quiz 88–9.Google Scholar
  109. 109.
    Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol. 2010;125(6):1202–5.PubMedCrossRefGoogle Scholar
  110. 110.
    Macaubas C, de Klerk NH, Holt BJ, Wee C, Kendall G, Firth M, et al. Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet. 2003;362(9391):1192–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, Johnston SL, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol. 2007;119(5):1105–10.PubMedCrossRefGoogle Scholar
  112. 112.
    Evans DJ, Barnes PJ, Spaethe SM, van Alstyne EL, Mitchell MI, O’Connor BJ. Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax. 1996;51(12):1178–84.PubMedCrossRefGoogle Scholar
  113. 113.
    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
  114. 114.
    Magrioti V, Kokotos G. Phospholipase A2 inhibitors as potential therapeutic agents for the treatment of inflammatory diseases. Expert Opin Ther Pat. 2010;20(1):1–18.PubMedCrossRefGoogle Scholar
  115. 115.
    Grant GE, Rokach J, Powell WS. 5-Oxo-ETE and the OXE receptor. Prostaglandins Other Lipid Mediat. 2009;89(3–4):98–104.PubMedCrossRefGoogle Scholar
  116. 116.
    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.Google Scholar
  117. 117.
    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
  118. 118.
    Philip G, van Adelsberg J, Loeys T, Liu N, Wong P, Lai E, et al. Clinical studies of the DP1 antagonist laropiprant in asthma and allergic rhinitis. J Allergy Clin Immunol. 2009;124(5):942–8.e1–9.Google Scholar
  119. 119.
    Shiga M, Horiguchi T, Kondo R, Miyazaki J, Hirose M, Otake Y, et al. Long-term monotherapy with suplatast tosilate in patients with mild atopic asthma: a pilot comparison with low-dose inhaled fluticasone. Asian Pac J Allergy Immunol. 2011;29(2):134–42.PubMedGoogle Scholar
  120. 120.
    Wada M, Nagata S, Kudo T, Shimizu T, Yamashiro Y. Effect of suplatast tosilate on antileukotriene non-responders with mild-to-moderate persistent asthma. Allergol Int. 2009;58(3):389–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Matsui E, Shinoda S, Fukutomi O, Kaneko H, Fukao T, Kondo N. Relationship between the benefits of suplatast tosilate, a Th2 cytokine inhibitor, and gene polymorphisms in children with bronchial asthma. Exp Ther Med. 2010;1(6):977–82.PubMedGoogle Scholar
  122. 122.
    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
  123. 123.
    Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125(6):1237–44.e2.Google Scholar
  124. 124.
    Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase 2 placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–8.Google Scholar
  125. 125.
    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
  126. 126.
    Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354(7):697–708.PubMedCrossRefGoogle Scholar
  127. 127.
    Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax. 2005;60(12):1012–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen 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
  129. 129.
    Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, Casteran N, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS ONE. 2009;4(9):e7258.PubMedCrossRefGoogle Scholar
  130. 130.
    Humbert M, de Blay F, Garcia G, Prud’homme A, Leroyer C, Magnan A, et al. Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy. 2009;64(8):1194–201.PubMedCrossRefGoogle Scholar
  131. 131.
    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.PubMedCrossRefGoogle Scholar
  132. 132.
    Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. 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
  133. 133.
    Gauvreau GM, Boulet LP, Schmid-Wirlitsch C, Cote J, Duong M, Killian KJ, et al. Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects. Respir Res. 2011;12:140.PubMedCrossRefGoogle Scholar
  134. 134.
    Page CP, Spina D. Selective PDE inhibitors as novel treatments for respiratory diseases. Curr Opin Pharmacol. 2012;12(3):275–86.PubMedCrossRefGoogle Scholar
  135. 135.
    Maneechotesuwan K, Ekjiratrakul W, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. 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):754–62.e1.Google Scholar
  136. 136.
    Moini A, Azimi G, Farivar A. Evaluation of atorvastatin for the treatment of patients with asthma: a double-blind randomized clinical trial. Allergy Asthma Immunol Res. 2012;4(5):290–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of Respiratory MedicineThe Children’s Hospital at WestmeadWestmeadAustralia
  2. 2.Faculty of Medicine, Discipline of Paediatrics and Child Health, The Children’s Hospital at Westmead Clinical School, Sydney Medical SchoolUniversity of SydneyWestmeadAustralia

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