, Volume 31, Issue 5, pp 393–408 | Cite as

Asthma Phenotypes and Endotypes: Implications for Personalised Therapy

  • Katrina Dean
  • Robert Niven
Leading Article


Asthma is increasingly recognised as a heterogeneous group of diseases with similar clinical presentations rather than a singular disease entity. Asthma was historically categorised by clinical symptoms; however, newer methods of subgrouping, describing and categorising the disease have sub-defined asthma. These sub-definitions are intermittently called phenotypes or endotypes, but the real meanings of these words are poorly understood. Novel treatments are currently and increasingly available, partly in the monoclonal antibody environment, and also some physical therapies (bronchial thermoplasty), but additionally small molecules are not far away from clinical practice. Understanding the disease pathogenesis and the mechanism of action more completely may enable identification of treatable traits, biomarkers, mediators and modifiable therapeutic targets. However, there remains a danger that clinicians become preoccupied with the concept of endotypes and biomarkers, ignoring therapies that are hugely effective but have no companion biomarker. This review discusses our understanding of the concept of phenotypes and endotypes in appreciating and managing the heterogeneous condition that is asthma. We consider the role of functional imaging, physiology, blood-, sputum- and breath-based biomarkers and clinical manifestations that could be used to produce a personalised asthma profile, with implications on prognosis, pathophysiology and most importantly specific therapeutic responses. With the advent of increasing numbers of biological therapies and other interventional options such as bronchial thermoplasty, the importance of targeting expensive therapies to patients with the best chance of clinical response has huge health economic importance.


Compliance with Ethical Standards


No funding was received for preparation of this manuscript.

Conflicts of interest

Katrina Dean reports no conflicts of interest. Robert Niven has received honorarium for speaker fees from AstraZeneca, Boehringer Ingelheim, Booston Scientific, Novartis, Napp, Teva and honorarium for advisory boards from AstraZeneca, Boehringer Ingelheim, Booston Scientific, Novartis, Teva and Vectura. RN has received support to attend international meetings from AstraZeneca, Boehringer Ingelheim, Cheisi and Novartis.


  1. 1.
    British Thoracic Society, Scottish Intercollegiate Guidance Network. British guideline on the management of asthma: a national clinical guideline. 2016. Accessed 08 Oct 2016.
  2. 2.
    Kiley J, Smith R, Noel P. Asthma phenotypes. Curr Opin Pulm Med. 2007;13(1):19–23.PubMedGoogle Scholar
  3. 3.
    Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med. 2004;10(1):44–50.PubMedCrossRefGoogle Scholar
  4. 4.
    Hekking PPW, Bel EH. Developing and emerging clinical asthma phenotypes. J Allergy Clin Immunol. 2014;2(6):671–80.CrossRefGoogle Scholar
  5. 5.
    Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Brit Med Bull. 2000;56(4):1054–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Lötvall J, Akdis CA, Bacharier LB, 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Wesolowska-Anderson A, Seibold MA. Airway molecular endotypes of asthma: dissecting the heterogeneity. Curr Opin Allergy Clin Immunol. 2015;15(2):163–8.CrossRefGoogle Scholar
  8. 8.
    George BJ, Reif DM, Gallagher JE, et al. Data-driven asthma endotypes defined from blood biomarker and gene expression data. PLoS One. 2015;10(2):e0117445. doi: 10.1371/journal.pone.0117445.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Agache I, Akdis C, Jutel M, et al. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835–46.PubMedCrossRefGoogle Scholar
  10. 10.
    Rajan JP, Wineinger NE, Stevenson DD, et al. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: a meta-analysis of the literature. J Allergy Clin Immunol. 2015;135(3):676–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Denning DW, O’Driscoll BR, Hogaboam CM, et al. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J. 2006;27:615–26.PubMedCrossRefGoogle Scholar
  12. 12.
    Farrant J, Brice H, Fowler S. Fungal sensitisation in severe asthma is associated with the identification of Aspergillus fumigatus in sputum. J Asthma. 2016;53(7):732–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Meyer N, Dallinga JW, Nuss S, et al. Defining adult asthma endotypes by clinical features and patterns of volatile organic compounds in exhaled air. Resp Res. 2014;15:136.CrossRefGoogle Scholar
  14. 14.
    Denning DW, O’Driscoll BR, Powell G, 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
  15. 15.
    Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Walford HH, Doherty TA. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014;7:53–65.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisolone-dependant asthma with sputum eosinophilia. N Engl J Med. 2009;360:985–93.PubMedCrossRefGoogle Scholar
  18. 18.
    Castro M, Zangrilli J, Wechsler ME, 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 Resp Med. 2015;3(5):355–66.CrossRefGoogle Scholar
  19. 19.
    Fitzgerald JM, Bleecker ER, Nair P, 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. doi: 10.1016/S0140-6736(16)31322-8.PubMedCentralGoogle Scholar
  20. 20.
    Wenzel S, Castro M, Coreen J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high dose inhaled corticosteroids pus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Resp Med. 2015;3(9):692–701.CrossRefGoogle Scholar
  22. 22.
    Gonem S, Berair R, Singapuri, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet. 2016;4(9):699–707.PubMedGoogle Scholar
  23. 23.
    Helenius I, Lumme A, Haahtela T. Asthma, airway inflammation and treatment in elite athletes. Sports Med. 2005;35(7):565–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Sestini P, Armetti L, Gambaro G, et al. Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma. Am J Respir Crit Care Med. 1996;153(2):572–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Picado C, Fernandez-Morata JC, Juan M, et al. Cyclooxygenase-2 mRNA is down expressed in nasal polyps from aspirin-sensitive asthmatics. Am J Respir Crit Care Med. 1999;160:291–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Szczeklsik A, Mastalerz L, Nizankowska E, et al. Protective and bronchodilator effects of prostaglandin E and salbutamol in aspirin-induced asthma. Am J Respir Crit Care Med. 1996;153(2):567–71.CrossRefGoogle Scholar
  27. 27.
    Sladek K, Szczeklik A. Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma. Eur Respir J. 1993;6:391–9.PubMedGoogle Scholar
  28. 28.
    Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis. 1991;143(5Pt1):1025–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Cowburn AS, Krzysztof S, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Investig. 1998;101(4):834–46.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Steinke JW, Borish L. Factors driving the aspirin exacerbated respiratory disease phenotype. Am J Rhinol Allergy. 2015;29(1):35–40.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Jinnai N, Sakagami T, Sekigawa T, et al. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet. 2004;13(24):3203–17.PubMedCrossRefGoogle Scholar
  32. 32.
    Liu T, Laidlaw TM, Katz HR, et al. Prostaglandin E2 deficiency causes and phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes. P Natl Acad Sci Biol. 2013;110(42):16987–92.CrossRefGoogle Scholar
  33. 33.
    Kim S-H, Oh J-M, Kim Y-S, et al. Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males. Clin Exp Allergy. 2006;36:433–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Laidlaw TM, Boyce JA. Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol Allergy Clin North Am. 2013;33(2):195–210.PubMedCrossRefGoogle Scholar
  35. 35.
    Izuhara K, Ohta S, Ono J. Using periostin as a biomarker in the treatment of asthma. Allergy Asthma Immunol Res. 2016;8(6):491–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Steinke JW, Wilson JM. Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances. J Asthma Allergy. 2016;9:37–43.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Levy JM, Rudmik L, Peters AT, et al. Contemporary management of chronic rhinosinusitis with nasal polyposis in aspirin-exacerbated respiratory disease: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2016;6(12):1273–83.Google Scholar
  38. 38.
    Knutsen AP, Slavin RG. Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis. Clin Dev Immunol. 2011;843763:1–14.CrossRefGoogle Scholar
  39. 39.
    Hogan C, Denning DW. Allergic bronchopulmonary aspergillosis and related allergic syndromes. Semin Respir Crit Care Med. 2011;32(6):682–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Agarwal R, Chakrabarti A, Shah A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013;43:850–73.PubMedCrossRefGoogle Scholar
  41. 41.
    Vincenzo AG, Chupp GL, Tsirilakis K, et al. CHIT1 mutations: genetic risk factor for severe asthma with fungal sensitization? Pediatrics. 2010;126(4):e982–5.CrossRefGoogle Scholar
  42. 42.
    Vaid M, Kaur S, Sambatakou H, et al. Distinct alleles of mannose binding lectin (MBL) and surfactant proteins A (SP-A) in patients with chronic cavitatory pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Clin Chem Lab Med. 2007;45(2):183–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Carvalho A, Pasqualotto AC, Pitzurra L, et al. Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis. J Infect Dis. 2008;197(4):618–21.PubMedCrossRefGoogle Scholar
  44. 44.
    Agarwal R, Khan A, Aggarwal AN, et al. Link between CFTR mutations and ABPA: a systematic review and meta-analysis. Mycoses. 2012;55(4):357–65.PubMedCrossRefGoogle Scholar
  45. 45.
    Chauhan B, Santiago L, Hutcheson PS, et al. Evidence for the involvement of two different MHC class II regions in susceptibility of protection in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2000;106(4):723–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Knutsen AP, Kariuki B, Concolino JD, et al. IL-4 alpha chain receptor (IL-4Rα) polymorphisms in allergic bronchopulmonary aspergillosis. Clin Mol Allergy. 2006;4(1):1–4.CrossRefGoogle Scholar
  47. 47.
    Godet C, Goudet V, Laurent F, et al. Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review. Mycoses. 2015;58:173–80.PubMedCrossRefGoogle Scholar
  48. 48.
    Chishimba L, Landridge P, Powell G, et al. Efficacy and safety of nebulised amphotericin B (NAB) in severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). J Asthma. 2015;52(3):289–95.PubMedCrossRefGoogle Scholar
  49. 49.
    Voskamp AL, Gillman A, Symons K, et al. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol: In Practice. 2015;3(2):192–9.CrossRefGoogle Scholar
  50. 50.
    Possa S, Leick EA, Prado CM, et al. Eosinophilic inflammation in allergic asthma. Front Pharmacol. 2013;4:46. doi: 10.3389/fphar.2013.00046.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Brightline CE. Eosinophils, bronchitis and asthma: pathogenesis of cough and airflow obstructions. Pulm Pharmacol Ther. 2011;24:324–7.CrossRefGoogle Scholar
  52. 52.
    Lemanske RF Jr, Busse WW. Asthma: clinical expression and molecular mechanisms. J Allergy Clin Immunol. 2010;125:S95–102.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kim Y-M, Kim Y-S, Jeon SG, et al. Immunopathogenesis of allergic asthma: more than the th2 hypothesis. Allergy Asthma Immunol Res. 2013;5(4):189–96.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kolsum U, Donaldson GC, Singh R, et al. Blood and sputum eosinophils in COPD; relationship with bacterial load. Respir Res. 2017;18:88. doi: 10.1186/s12931-017-0570-5.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Slager RE, Li H, Moore W, et al. Predictive model of severe atopic asthma phenotypes using interleukin 4/13 pathway polymorphisms. In: American Thoracic Society International Conference. A33. Genetic and Epigenetic Regulation of Lung Disease. 2011, A1332.Google Scholar
  56. 56.
    Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007;448:470–3.PubMedCrossRefGoogle Scholar
  57. 57.
    Andiappan AK, Sio YY, Lee B, et al. Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis. J Allergy Clin Immunol. 2016;137(3):758–66.PubMedCrossRefGoogle Scholar
  58. 58.
    Michel S, Busato F, Genuneit J, et al. Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy. 2013;68(3):355–64.PubMedCrossRefGoogle Scholar
  59. 59.
    Klaassen EMM, Penders J, Jöbsis Q, et al. An ADAM33 polymorphisms associated with progression of preschool wheeze into childhood asthma: a prospective case control study with replication in a birth cohort study. PLoS One. 2015;10(3):e0119349.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Holgate ST, Davies DE, Murphy G, et al. ADAM33: just another asthma gene or a breakthrough in understanding the origins of bronchial hyperresponsiveness? Thorax. 2003;58(6):466–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Durham AL, Caramoiri G, Chung KF, et al. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease. Transl Res. 2016;167(1):192–203.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Resp J. 2014;43:343–73.CrossRefGoogle Scholar
  63. 63.
    D’Hooghe JNS, De Bruin DM, Wijmans L, et al. Bronchial wall thickness assessed by optical coherence tomography (OCT) before and after bronchial thermoplasty (BT). Eur Respir J. 2015;46(59):OA1763.Google Scholar
  64. 64.
    Salam MT, Wenten M, Gilliland FD. Endogenous sex steroid hormones and asthma and wheeze in young women. J allergy Clin Immunol. 2006;117(5):100–7.CrossRefGoogle Scholar
  65. 65.
    Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations and the risk of adult-onset asthma. A prospective cohort study. Am J Crit Care Med. 1995;152(4):1183–8.CrossRefGoogle Scholar
  66. 66.
    Nahm D-H, Lee K-H, Shin J-Y, et al. Identification of α-enolase as an autoantigen associated with severe asthma. J Allergy Clin Immunol. 2006;118(2):376–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Nahm D-H, Lee Y-E, Yim E-J, et al. Identification of cytokeratin 18 as a bronchial epithelial autoantigen associated with nonallergic asthma. Am J Respir Crit Care Med. 2002;165(11):1536–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Hizawa N, Yamaguchi E, Konno S, et al. A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma. Am J Resp Crit Care Med. 2002;166(5):686–90.PubMedCrossRefGoogle Scholar
  69. 69.
    Taniguchi N, Konno S, Hattori T, et al. The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma. Ann Allergy Asthma Immunol. 2013;111(5):376–81.PubMedCrossRefGoogle Scholar
  70. 70.
    Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–25.PubMedCrossRefGoogle Scholar
  71. 71.
    Coleman JM, Naik C, Holguin F, et al. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age of onset. Thorax. 2012;201634:1–6.Google Scholar
  72. 72.
    Labrador-Horillo M, Ramentol M, Martinez-Valle F, et al. Eotaxin is overexpressed in Churg-Strauss syndrome compared to allergic asthma. Ann Rheum Dis. 2013;72:A800.CrossRefGoogle Scholar
  73. 73.
    Schwartz LB, Delgado L, Craig T, et al. Exercise-induced hypersensitivity syndromes in recreational and competitive athletes: a PRACTALL consensus report (what the general practitioner should know about sports and allergy). Allergy. 2008;63(8):953–61.PubMedCrossRefGoogle Scholar
  74. 74.
    Karjalainen EM, Laitinen A, Sue-Chu M, et al. Evidence of airway inflammation and remodelling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med. 2000;161:2086–91.PubMedCrossRefGoogle Scholar
  75. 75.
    Carlsen KH. Mechanism of asthma development in elite athletes. Breathe. 2012;8(4):279–84.CrossRefGoogle Scholar
  76. 76.
    Carlsen KH, Anderson SD, Bjermer L, et al. Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part 1 of the report from the joint task force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy. 2008;63(4):387–403.PubMedCrossRefGoogle Scholar
  77. 77.
    Hallstrand TS, Moody MW, Wurfel MM, et al. Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2005;172(6):679–86.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Bougault V, Turmel J, St-Laurent J, et al. Asthma, airway inflammation and epithelial damage in swimmers and cold air athletes. Eur Respir J. 2009;33:740–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Chimenti L, Morici G, Paternò A, et al. Bronchial epithelial damage after a half-marathon in nonasthmatic amateur runners. Am J Physiol Lung C. 2010;298(6):L857–62.CrossRefGoogle Scholar
  80. 80.
    Carlsen KH. Sports in extreme conditions: the impact of exercise in cold temperatures on asthma and bronchial hyper-responsiveness in athletes. Brit J Sport Med. 2012;46:796–9.CrossRefGoogle Scholar
  81. 81.
    Pelaia G, Vatrella A, Busceti MT, et al. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediat Inflamm. 2015;879783:1–8.CrossRefGoogle Scholar
  82. 82.
    Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J. 2013;41:716–26.PubMedCrossRefGoogle Scholar
  83. 83.
    Newcomb DC, Stokes-Peebles R Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol. 2013;25(6):1–12.CrossRefGoogle Scholar
  84. 84.
    Al-ramil W, Préfontaine D, Chouiali F, et al. Th17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.CrossRefGoogle Scholar
  85. 85.
    Yang XO, Chang SH, Park H, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063–75.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Hoskins A, Reiss S, Wu P, et al. Asthmatic airway neutrophilia after allergen challenge is associated with the glutathione S-transferase M1 genotype. Am J Resp Crit Care Med. 2013;187(1):34–41.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kawaguchi M, Takahashi D, Hizawa N, et al. IL-17F sequence variant (HI161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol. 2006;117(4):795–801.PubMedCrossRefGoogle Scholar
  88. 88.
    Desai D, Gupta S, Siddiqui S, et al. Sputum mediator profiling and relationship to airway wall geometry imaging in severe asthma. Resp Res. 2013;14(17):1–13.Google Scholar
  89. 89.
    Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148–55.PubMedCrossRefGoogle Scholar
  90. 90.
    Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomised placebo-controlled clinical trial. Clin Exp Allergy. 2012;42(7):1097–103.PubMedCrossRefGoogle Scholar
  91. 91.
    Bruijnzeel PLB, Uddin M, Koenderman L. Targeting neutrophilic inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil phenotype? J Leukocyte Biol. 2015;98(4):549–56.PubMedCrossRefGoogle Scholar
  92. 92.
    Meyer N, Dallinga JW, Nuss S, et al. Defining adult asthma endotypes by clinical features and patterns of volatile organic compounds in exhaled air. Resp Res. 2014;15:136.CrossRefGoogle Scholar
  93. 93.
    Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Resp Crit Care Med. 2010;181(4):315–23.PubMedCrossRefGoogle Scholar
  94. 94.
    Moore WC, Li X, Li H, et al. Clinical cluster phenotypes from the Severe Asthma Research Program (SARP1/2): reproducibility in SARP 3 and the importance of baseline lung function in disease stability and progression. Am J Respir Crit Care Med. 2016;193:A7852.Google Scholar
  95. 95.
    Wu W, Bleecker ER, Meyers DA, et al. Differential response to systemic corticosteroids as assessed by cluster analysis of data from the Severe Asthma Research Program (SARP). Am J Respir Crit Care Med. 2017;195:A1362.CrossRefGoogle Scholar
  96. 96.
    Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–24.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Car Med. 2010;181:315–23.CrossRefGoogle Scholar
  98. 98.
    Hastie A, Mauger D, Denlinger LC, et al. Sputum and blood eosinophil and neutrophil associations with a more severe asthma phenotype in the NHLBI Severe Asthma Research Program (SARP). Am J Respir Crit Care Med. 2017;195:A4695.Google Scholar
  99. 99.
    Schatz M, Hsu JWY, Zeiger RS. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2014;133:1549–56.PubMedCrossRefGoogle Scholar
  100. 100.
    Ortega H, Li H, Suruki R. Cluster analysis and characterisation of response to mepolizumab: a step closer to personalised medicine for patients with severe asthma. Ann Am Thorac Soc. 2014;11(7):1011–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Thien F. Measuring and imaging small airways dysfunction in asthma. Asia Pac Allergy. 2013;3(4):224–30.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Zhang WJ, Niven RM, Young SS, et al. Dynamic oxygen-enhanced magnetic resonance imaging of the lung in asthma—initial experience. Eur J Radiol. 2015;84:318–26.PubMedCrossRefGoogle Scholar
  103. 103.
    Aysola R, de Lange EE, Castro M, et al. Demonstration of the heterogeneous distribution of asthma in the lungs using CT and hyperpolarized helium-3 MRI. J Magn Reson Imaging. 2010;32(6):1379–87.PubMedCrossRefGoogle Scholar
  104. 104.
    Thomen RP, Sheshadri A, Quirk JD, et al. Regional ventilation changes in severe asthma after bronchial thermoplasty with 3He MR imaging and CT. Radiology. 2015;274(1):250–9.PubMedCrossRefGoogle Scholar
  105. 105.
    NHS England. Service specification: specialised respiratory services (adult)—severe asthma. Accessed 13/11/2016.
  106. 106.
    Little SA, Sproule MW, Cowan MD, et al. High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity. Thorax. 2002;57:247–53.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Menzies D, Holmes L, McCumesky G, et al. Aspergillus sensitization is associated with airflow limitation and bronchiectasis in severe asthma. Allergy. 2011;66(5):679–85.PubMedCrossRefGoogle Scholar
  108. 108.
    Laxmanan B, Hogarth DK. Bronchial thermoplasty in asthma: current perspectives. J asthma allergy. 2015;8:39–49.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Jung JW, Kwon JW, Kim TW, et al. New insight into the assessment of asthma using xenon ventilation computed tomography. Ann Allergy Asthma Immunol. 2013;111(2):90–5.PubMedCrossRefGoogle Scholar
  110. 110.
    Oostveen E, MacLeod D, Lorino H, et al. The forced oscillation technique in clinical practice: methodology, recommendations and future development. Eur Resp J. 2003;22:1026–41.CrossRefGoogle Scholar
  111. 111.
    McLaughlin RA, Noble PB, Sampson DD. Optical coherence tomography in respiratory science and medicine: from airways to alveoli. Physiology. 2014;29(5):369–80.PubMedCrossRefGoogle Scholar
  112. 112.
    Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21.PubMedCrossRefGoogle Scholar
  113. 113.
    Brightling CE, Green RH, Pavord ID. Biomarkers predicting response to corticosteroid therapy in asthma. Treatments Respir Med. 2005;4(5):309–16.CrossRefGoogle Scholar
  114. 114.
    Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Resp Med. 2015;3(4):290–300.CrossRefGoogle Scholar
  115. 115.
    Powell C, Milan SJ, Dwan K, et al. Mepolizumab versus placebo for asthma. Cochrane DB Syst Rev. 2015;27(7):CD010834.Google Scholar
  116. 116.
    Bousquet J, Rabe K, Humbert M, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med. 2007;101(7):1483–92.PubMedCrossRefGoogle Scholar
  117. 117.
    Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–98.PubMedCrossRefGoogle Scholar
  118. 118.
    Chiappori A, De Ferrari L, Folli C, et al. Biomarkers and severe asthma: a critical appraisal. Clin Mol Allergy. 2015;13(20):1–11.Google Scholar
  119. 119.
    Gemicioglu B, Musellim B, Dogan I, et al. Fractional exhaled nitric oxide (FeNo) in different asthma phenotypes. Allergy Rhinol. 2014;5:e157–61.CrossRefGoogle Scholar
  120. 120.
    Hanania NA, Wenzel S, Resén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Resp Crit Care Med. 2013;187(8):804–11.PubMedCrossRefGoogle Scholar
  121. 121.
    Hanania NA, Korenblat P, Chapman KR, 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
  122. 122.
    Vijverberg SJH, Hilvering B, Raaijmakers JAM, et al. Clinical utility of asthma biomarkers: from bench to bedside. Biol: Targets Ther. 2013;7:199–210.Google Scholar
  123. 123.
    Wang W, Li Y, Lv Z, et al. The Th2 cell-promoting cytokines IL-33 and TSLP, but not IL-25 are potential biomarkers for endotypes of asthma. Chest. 2016;149(4S):A34.CrossRefGoogle Scholar
  124. 124.
    Miligkos M, Bannuru RR, Alkofide H, et al. Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: a systematic review and meta-analysis. Ann Intern Med. 2015;163(10):756–67.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Mastalerz L, Nizankowska E, Sanak M, et al. Clinical and genetic features underlying the response of patients with bronchial asthma to treatment with a leukotriene receptor antagonist. Eur J Clin Investig. 2002;32(12):949–55.CrossRefGoogle Scholar
  126. 126.
    Kane B, Fowler SJ, Niven RM. Refractory asthma—beyond step 5, the role of new and emerging adjuvant therapies. Chronic Resp Dis. 2015;12(1):69–77.CrossRefGoogle Scholar
  127. 127.
    Kew KM, Undela K, Kotortsi I, et al. Macrolides for chronic asthma (review). Cochrane DB Syst Rev. 2015;9:CD002997.Google Scholar
  128. 128.
    Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; In press.
  129. 129.
    Deeks ED. Mepolizumab: a review in eosinophilic asthma. Biodrugs. 2016;30(4):361–70.PubMedCrossRefGoogle Scholar
  130. 130.
    Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockage in severe persistent asthma. Am J Resp Crit Care Med. 2009;179(7):549–58.PubMedCrossRefGoogle Scholar
  131. 131.
    Bice JB, Leechawengwongs E, Montanaro A, et al. Biologic targeted therapy in asthma. Ann Allergy Asthma Immunol. 2014;112:108–15.PubMedCrossRefGoogle Scholar
  132. 132.
    Slager RE, Otulana BA, Hawkins GA, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J Allergy Clin Immunol. 2012;130(2):516–22.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Gauvreau GM, O’Byrne PM, Boulet LP, et al. Effects of an Anti-TSLP antibody on allergen-induced asthmatic response. N Engl J Med. 2014;370:2102–10.PubMedCrossRefGoogle Scholar
  134. 134.
    Pretolani M, Bergqvist A, Thabut G, et al. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathological correlations. J Allergy Clin Immunol. 2016. doi: 10.1016/j.jaci.2016.08.009.Google Scholar
  135. 135.
    Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Clin Immunol. 2013;132(6):1295–302.CrossRefGoogle Scholar
  136. 136.
    Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J. 2008;32(3):545–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.University Hospital South ManchesterManchesterUK
  2. 2.Manchester Academic Health Science CentreThe University of Manchester and University Hospital South ManchesterManchesterUK

Personalised recommendations