Drugs

, Volume 74, Issue 7, pp 719–728 | Cite as

Defining Phenotypes in Asthma: A Step Towards Personalized Medicine

Current Opinion

Abstract

Asthma is a common disease with a complex pathophysiology. It can present in various clinical forms and with different levels of severity. Unbiased cluster analytic methods have unravelled several phenotypes in cohorts representative of the whole spectrum of severity. Clusters of severe asthma include those on high-dose corticosteroid treatment, often with both inhaled and oral treatment, usually associated with severe airflow obstruction. Phenotypes with concordance between symptoms and sputum eosinophilia have been reported, including an eosinophilic inflammation-predominant group with few symptoms and late-onset disease who have a high prevalence of rhinosinusitis, aspirin sensitivity, and exacerbations. Sputum eosinophilia is also a biomarker that can predict therapeutic responses to antibody-based treatments to block the effects of the T-helper (Th)-2 cytokine, interleukin (IL)-5. Low Th2-expression has been predictive of poor therapeutic response to inhaled corticosteroid therapy. Current asthma schedules emphasise a step-up approach to treating asthma in relation to increasing severity, but, in more severe disease, phenotyping or endotyping of asthma will be necessary to determine new treatment strategies as severe asthma is recognized as being a particularly heterogeneous disease. Much less is known about ‘non-eosinophilic’ asthma. Phenotypic characterisation of corticosteroid insensitivity and chronic airflow obstruction of severe asthma is also needed. Phenotype-driven treatment of asthma will be further boosted by the advent of transcriptomic and proteomic technologies, with the application of systems biology or medicine approaches to defining phenotypes and biomarkers of disease and therapeutic response. This will pave the way towards personalized medicine and healthcare for asthma.

References

  1. 1.
    Bel EH. Clinical phenotypes of asthma. Curr Opin Pulmonary Med. 2004;10(1):44–50.CrossRefGoogle Scholar
  2. 2.
    Chung KF, Godard P, Adelroth E, Ayres J, Barnes N, Barnes P, et al. Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma European Respiratory Society. Eur Respir J. 1999;13(5):1198–208.PubMedGoogle Scholar
  3. 3.
    Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162(6):2341–51.Google Scholar
  4. 4.
    Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107–19.CrossRefPubMedGoogle Scholar
  5. 5.
    Lotvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355–60.CrossRefPubMedGoogle Scholar
  6. 6.
    Prosperi MC, Sahiner UM, Belgrave D, Sackesen C, Buchan IE, Simpson A, et al. Challenges in identifying asthma subgroups using unsupervised statistical learning techniques. Am J Respir Crit Care Med. 2013;188(11):1303–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315–23.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, et al. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol. 2011;127(2):382–389.e1-13.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218–24.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Siroux V, Basagana X, Boudier A, Pin I, Garcia-Aymerich J, Vesin A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J. 2011;38(2):310–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim TB, Jang AS, Kwon HS, Park JS, Chang YS, Cho SH, et al. Identification of asthma clusters in two independent Korean adult asthma cohorts. Eur Respir J. 2013;41(6):1308–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Kaneko Y, Masuko H, Sakamoto T, Iijima H, Naito T, Yatagai Y, et al. Asthma phenotypes in Japanese adults—their associations with the CCL5 and ADRB2 genotypes. Allergol Int. 2013;62(1):113–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Patrawalla P, Kazeros A, Rogers L, Shao Y, Liu M, Fernandez-Beros ME, Shang S, Reibman J. Application of the asthma phenotype algorithm from the Severe Asthma Research Program to an urban population. PLoS ONE. 2012;7(9):e44540.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Chang TS, Lemanske RF Jr, Mauger DT, Fitzpatrick AM, Sorkness CA, Szefler SJ, et al. Childhood asthma clusters and response to therapy in clinical trials. J Allergy Clin Immunol. 2014;133:363–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Schatz M, Hsu JW, Zeiger RS, Chen W, Dorenbaum A, Chipps BE, et al. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2013 Dec 3 [Epub ahead of print].Google Scholar
  16. 16.
    Jang AS, Kwon HS, Cho YS, Bae YJ, Kim TB, Park JS, et al. Identification of subtypes of refractory asthma in Korean patients by cluster analysis. Lung. 2013;191(1):87–93.CrossRefPubMedGoogle Scholar
  17. 17.
    Sutherland ER, Goleva E, King TS, Lehman E, Stevens AD, Jackson LP, et al. Cluster analysis of obesity and asthma phenotypes. PLoS ONE. 2012;7(5):e36631.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Gibeon D, Batuwita K, Osmond M, Heaney LG, Brightling CE, Niven R, et al. Obesity-associated severe asthma represents a distinct clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest. 2013;143(2):406–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Amelink M, de Nijs SB, de Groot JC, van Tilburg PM, van Spiegel PI, Krouwels FH, et al. Three phenotypes of adult-onset asthma. Allergy. 2013;68(5):674–80.CrossRefPubMedGoogle Scholar
  20. 20.
    Boudier A, Curjuric I, Basagana X, Hazgui H, Anto JM, Bousquet J, et al. Ten-year follow-up of cluster-based asthma phenotypes in adults. A pooled analysis of three cohorts. Am J Respir Crit Care Med. 2013;188(5):550–60.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    Chung KF, Caramori G, Adcock IM. Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol. 2009;65(9):853–71.CrossRefPubMedGoogle Scholar
  23. 23.
    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;43:343–73.CrossRefPubMedGoogle Scholar
  24. 24.
    Deykin A, Lazarus SC, Fahy JV, Wechsler ME, Boushey HA, Chinchilli VM, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005;115(4):720–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65(5):384–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Dente FL, Bacci E, Bartoli ML, Cianchetti S, Costa F, Di Franco A, et al. Effects of oral prednisone on sputum eosinophils and cytokines in patients with severe refractory asthma. Ann Allergy Asthma Immunol. 2010;104(6):464–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2013 Dec 8 [Epub ahead of print].Google Scholar
  29. 29.
    Israel E, Chervinsky PS, Friedman B, van Bavel J, Skalky CS, Ghannam AF, et al. Effects of montelukast and beclomethasone on airway function and asthma control. J Allergy Clin Immunol. 2002;110(6):847–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1532–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168(11):1308–11.CrossRefPubMedGoogle Scholar
  32. 32.
    Sutherland ER, Goleva E, Strand M, Beuther DA, Leung DY. Body mass and glucocorticoid response in asthma. Am J Respir Crit Care Med. 2008;178(7):682–7.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Wysocki K, Park SY, Bleecker E, Busse W, Castro M, Chung KF, et al. Characterization of factors associated with systemic corticosteroid use in severe asthma: data from the Severe Asthma Research Program. J Allergy Clin Immunol. 2014;133:915–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Chang PJ, Bhavsar PK, Michaeloudes C, Khorasani N, Chung KF. Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma. J Allergy Clin Immunol. 2012;130(4):877–885.e5.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF. Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J. 2010;35(4):750–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. 2001;15(6):1110–2.PubMedGoogle Scholar
  37. 37.
    Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. 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.CrossRefPubMedGoogle Scholar
  38. 38.
    Leung DYM, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. 1997;186(9):1567–74.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med. 2012;185(6):612–9.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160(3):1001–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J Allergy Clin Immunol. 2011;127(1):153–160.e1-9.CrossRefPubMedGoogle Scholar
  42. 42.
    Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010;125(5):1028–1036.e13.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Zhang Q, Illing R, Hui CK, Downey K, Carr D, Stearn M, et al. Bacteria in sputum of stable severe asthma and increased airway wall thickness. Respir Res. 2012;13:35.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Wood LG, Simpson JL, Hansbro PM, Gibson PG. Potentially pathogenic bacteria cultured from the sputum of stable asthmatics are associated with increased 8-isoprostane and airway neutrophilia. Free Radic Res. 2010;44(2):146–54.CrossRefPubMedGoogle Scholar
  45. 45.
    Fitzpatrick AM, Holguin F, Teague WG, Brown LA. Alveolar macrophage phagocytosis is impaired in children with poorly controlled asthma. J Allergy Clin Immunol. 2008;121(6):1372–8.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Huynh ML, Malcolm KC, Kotaru C, Tilstra JA, Westcott JY, Fadok VA, et al. Defective apoptotic cell phagocytosis attenuates PGE2 and 15-HETE in severe asthma alveolar macrophages. Am J Respir Crit Care Med. 2005;172:972–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Nguyen LT, Lim S, Oates T, Chung KF. Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir Med. 2005;99(2):200–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemiere C, Foley S, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest. 2008;133(2):420–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA. 2007;104(40):15858–63.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify T2-high and T2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133:388–94.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Adcock IM, Caramori G, Chung KF. New targets for drug development in asthma. Lancet. 2008;372(9643):1073–87.CrossRefPubMedGoogle Scholar
  54. 54.
    Holgate ST. Innate and adaptive immune responses in asthma. Nat Med. 2012;18(5):673–83.CrossRefPubMedGoogle Scholar
  55. 55.
    Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med. 2013;1:639–52.CrossRefPubMedGoogle Scholar
  56. 56.
    Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309–16.CrossRefPubMedGoogle Scholar
  57. 57.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    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.CrossRefPubMedGoogle Scholar
  59. 59.
    Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804–11.CrossRefPubMedGoogle Scholar
  60. 60.
    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.CrossRefPubMedGoogle Scholar
  61. 61.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    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.CrossRefPubMedGoogle Scholar
  63. 63.
    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.CrossRefPubMedGoogle Scholar
  64. 64.
    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.CrossRefPubMedGoogle Scholar
  65. 65.
    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.CrossRefPubMedGoogle Scholar
  66. 66.
    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.CrossRefPubMedGoogle Scholar
  67. 67.
    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;368:2455–66.CrossRefPubMedGoogle Scholar
  68. 68.
    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.CrossRefPubMedGoogle Scholar
  69. 69.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    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):1097–103.CrossRefPubMedGoogle Scholar
  71. 71.
    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.CrossRefPubMedGoogle Scholar
  72. 72.
    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.CrossRefPubMedGoogle Scholar
  73. 73.
    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.CrossRefPubMedGoogle Scholar
  74. 74.
    Gibeon D, Chung KF. The investigation of severe asthma to define phenotypes. Clin Exp Allergy. 2012;42(5):678–92.CrossRefPubMedGoogle Scholar
  75. 75.
    Chung KF. Inflammatory biomarkers in severe asthma. Curr Opin Pulmonary Med. 2012;18(1):35–41.CrossRefGoogle Scholar
  76. 76.
    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.CrossRefPubMedGoogle Scholar
  77. 77.
    Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130(3):647–654.e10.PubMedCentralCrossRefPubMedGoogle Scholar
  78. 78.
    Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132(2):305–312.e3.CrossRefPubMedGoogle Scholar
  79. 79.
    Saito J, Zhang Q, Hui C, Macedo P, Gibeon D, Menzies-Gow A, et al. Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma. J Allergy Clin Immunol. 2013;131(1):232–234.e1-3.CrossRefPubMedGoogle Scholar
  80. 80.
    Kabesch M, Adcock IM. Epigenetics in asthma and COPD. Biochimie. 2012;94(11):2231–41.CrossRefPubMedGoogle Scholar
  81. 81.
    Tsitsiou E, Williams AE, Moschos SA, Patel K, Rossios C, Jiang X, et al. Transcriptome analysis shows activation of circulating CD8+ T cells in patients with severe asthma. J Allergy Clin Immunol. 2012;129(1):95–103.CrossRefPubMedGoogle Scholar
  82. 82.
    O’Neil SE, Sitkauskiene B, Babusyte A, Krisiukeniene A, Stravinskaite-Bieksiene K, Sakalauskas R, et al. Network analysis of quantitative proteomics on asthmatic bronchi: effects of inhaled glucocorticoid treatment. Respir Res. 2011;12:124.PubMedCentralCrossRefPubMedGoogle Scholar
  83. 83.
    Hwang S, Son SW, Kim SC, Kim YJ, Jeong H, Lee D. A protein interaction network associated with asthma. J Theor Biol. 2008;252(4):722–31.CrossRefPubMedGoogle Scholar
  84. 84.
    Auffray C, Adcock IM, Chung KF, Djukanovic R, Pison C, Sterk PJ. An integrative systems biology approach to understanding pulmonary diseases. Chest. 2010;137(6):1410–6.CrossRefPubMedGoogle Scholar
  85. 85.
    Chen R, Snyder M. Systems biology: personalized medicine for the future? Curr Opin Pharmacol. 2012;12(5):623–8.CrossRefPubMedGoogle Scholar
  86. 86.
    Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152(4):714–26.PubMedCentralCrossRefPubMedGoogle Scholar
  87. 87.
    Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363(4):301–4.CrossRefPubMedGoogle Scholar
  88. 88.
    Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59–99.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Experimental Studies, National Heart and Lung InstituteImperial College LondonLondonUK
  2. 2.Royal Brompton NIHR Biomedical Research UnitLondonUK

Personalised recommendations