Clinical Reviews in Allergy & Immunology

, Volume 56, Issue 2, pp 219–233 | Cite as

Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease

  • Merin E. Kuruvilla
  • F. Eun-Hyung Lee
  • Gerald B. LeeEmail author


The model of asthma as a single entity has now been replaced by a much more complex biological network of distinct and interrelating inflammatory pathways. The term asthma is now considered an umbrella diagnosis for several diseases with distinct mechanistic pathways (endotypes) and variable clinical presentations (phenotypes). The precise definition of these endotypes is central to asthma management due to inherent therapeutic and prognostic implications. This review presents the molecular mechanisms behind the heterogeneity of airway inflammation in asthmatic patients. Asthma endotypes may be broadly regarded as type 2 (T2) high or T2-low. Several biologic agents have been approved for T2-high asthma, with numerous other therapeutics that are incipient and similarly targeted at specific molecular mechanisms. Collectively, these advances have shifted existing paradigms in the approach to asthma to tailor novel therapies.


Asthma Phenotypes Endotypes T2 disease Non-T2 disease 



We would like to thank Sandhya Khurana and Jen Kwong for their excellent comments on the manuscript.

Compliance with Ethical Standards

Conflict of Interest

F.E.-H.L. is the founder of MicroBplex, Inc. M.E.K. and G.B.L. have no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

Not applicable.


  1. 1.
    Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL et al (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160(3):1001–1008Google Scholar
  2. 2.
    Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE (2004) Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 113(1):101–108Google Scholar
  3. 3.
    Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER, National Heart, Lung, and Blood Institute's Severe Asthma Research Program (2010) Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med 181(4):315–323Google Scholar
  4. 4.
    Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, Pandis I, Bansal AT, Bel EH, Auffray C, Compton CH, Bisgaard H, Bucchioni E, Caruso M, Chanez P, Dahlén B, Dahlen SE, Dyson K, Frey U, Geiser T, Gerhardsson de Verdier M, Gibeon D, Guo YK, Hashimoto S, Hedlin G, Jeyasingham E, Hekking PP, Higenbottam T, Horváth I, Knox AJ, Krug N, Erpenbeck VJ, Larsson LX, Lazarinis N, Matthews JG, Middelveld R, Montuschi P, Musial J, Myles D, Pahus L, Sandström T, Seibold W, Singer F, Strandberg K, Vestbo J, Vissing N, von Garnier C, Adcock IM, Wagers S, Rowe A, Howarth P, Wagener AH, Djukanovic R, Sterk PJ, Chung KF, U-BIOPRED Study Group (2015) Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 46(5):1308–1321Google Scholar
  5. 5.
    Loza MJ, Djukanovic R, Chung KF, Horowitz D, Ma K, Branigan P et al (2016) Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res 17(1):165Google Scholar
  6. 6.
    Heijink IH, Kies PM, Kauffman HF, Postma DS, van Oosterhout AJ, Vellenga E (2007) Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity. J Immunol 178(12):7678–7685Google Scholar
  7. 7.
    Sweerus K, Lachowicz-Scroggins M, Gordon E, LaFemina M, Huang X, Parikh M, Kanegai C, Fahy JV, Frank JA (2017) Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J Allergy Clin Immunol 139(1):72–81.e1Google Scholar
  8. 8.
    Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, GABRIEL Consortium (2010) A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 363(13):1211–1221Google Scholar
  9. 9.
    Guo Z, Wu J, Zhao J, Liu F, Chen Y, Bi L, Liu S, Dong L (2014) IL-33 promotes airway remodeling and is a marker of asthma disease severity. J Asthma 51(8):863–869Google Scholar
  10. 10.
    Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174(12):8183–8190Google Scholar
  11. 11.
    Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, Lemiere C, Martin JG, Hamid Q (2009) Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol 183(8):5094–5103Google Scholar
  12. 12.
    Cheng D, Xue Z, Yi L, Shi H, Zhang K, Huo X, Bonser LR, Zhao J, Xu Y, Erle DJ, Zhen G (2014) Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med 190(6):639–648Google Scholar
  13. 13.
    Al-Sajee D, Sehmi R, Hawke TJ, El-Gammal A, Howie KJ, Watson RM et al (2018) The expression of IL-33 and TSLP and their receptors in asthmatic airways following inhaled allergen challenge. Am J Respir Crit Care MedGoogle Scholar
  14. 14.
    Yang Q, Ge MQ, Kokalari B, Redai IG, Wang X, Kemeny DM, Bhandoola A, Haczku A (2016) Group 2 innate lymphoid cells mediate ozone-induced airway inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol 137(2):571–578Google Scholar
  15. 15.
    Chen R, Smith SG, Salter B, El-Gammal A, Oliveria JP, Obminski C et al (2017) Allergen-induced increases in sputum levels of group 2 innate lymphoid cells in subjects with asthma. Am J Respir Crit Care Med 196(6):700–712Google Scholar
  16. 16.
    Hirose K, Iwata A, Tamachi T, Nakajima H (2017) Allergic airway inflammation: key players beyond the Th2 cell pathway. Immunol Rev 278(1):145–161Google Scholar
  17. 17.
    Guo L, Huang Y, Chen X, Hu-Li J, Urban JF Jr, Paul WE (2015) Innate immunological function of TH2 cells in vivo. Nat Immunol 16(10):1051–1059Google Scholar
  18. 18.
    Paul WE (2010) What determines Th2 differentiation, in vitro and in vivo? Immunol Cell Biol 88(3):236–239Google Scholar
  19. 19.
    Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125(2):S73–S80Google Scholar
  20. 20.
    Persson C (2013) Lysis of primed eosinophils in severe asthma. J Allergy Clin Immunol 132(6):1459–1460Google Scholar
  21. 21.
    Durrani SR, Viswanathan RK, Busse WW (2011) What effect does asthma treatment have on airway remodeling? Current perspectives. J Allergy Clin Immunol 128(3):439–448 quiz 49-50Google Scholar
  22. 22.
    Chung KF (2000) Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation? Eur Respir J 15(5):961–968Google Scholar
  23. 23.
    Cayrol C, Girard JP (2018) Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 281(1):154–168Google Scholar
  24. 24.
    Fanning LB, Boyce JA (2013) Lipid mediators and allergic diseases. Ann Allergy Asthma Immunol 111(3):155–162Google Scholar
  25. 25.
    Kim BS, Wang K, Siracusa MC, Saenz SA, Brestoff JR, Monticelli LA, Noti M, Tait Wojno ED, Fung TC, Kubo M, Artis D (2014) Basophils promote innate lymphoid cell responses in inflamed skin. J Immunol 193(7):3717–3725Google Scholar
  26. 26.
    Kim BS, Wojno ED, Artis D (2013) Innate lymphoid cells and allergic inflammation. Curr Opin Immunol 25(6):738–744Google Scholar
  27. 27.
    Kepley CL, McFeeley PJ, Oliver JM, Lipscomb MF (2001) Immunohistochemical detection of human basophils in postmortem cases of fatal asthma. Am J Respir Crit Care Med 164(6):1053–1058Google Scholar
  28. 28.
    Macfarlane AJ, Kon OM, Smith SJ, Zeibecoglou K, Khan LN, Barata LT, McEuen AR, Buckley MG, Walls AF, Meng Q, Humbert M, Barnes NC, Robinson DS, Ying S, Kay AB (2000) Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin. J Allergy Clin Immunol 105(1 Pt 1):99–107Google Scholar
  29. 29.
    Samitas K, Delimpoura V, Zervas E, Gaga M (2015) Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives. Eur Respir Rev 24(138):594–601Google Scholar
  30. 30.
    Brown JM, Wilson TM, Metcalfe DD (2008) The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy 38(1):4–18Google Scholar
  31. 31.
    Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E, Busse WW et al (2011) Mast cell phenotype, location, and activation in severe asthma. Data from the severe asthma research program. Am J Respir Crit Care Med 183(3):299–309Google Scholar
  32. 32.
    Fajt ML, Gelhaus SL, Freeman B, Uvalle CE, Trudeau JB, Holguin F, Wenzel SE (2013) Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol 131(6):1504–1512Google Scholar
  33. 33.
    Peters MC, Kerr S, Dunican EM, Woodruff PG, Fajt ML, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Hastie AT, Bleecker ER, Wenzel SE, Fahy JV (2018) Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J Allergy Clin ImmunolGoogle Scholar
  34. 34.
    Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H et al (2016) Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol 137(5):1449–56.e4Google Scholar
  35. 35.
    Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, Bleecker ER, National Heart, Lung, and Blood Institute Severe Asthma Research Program (2010) Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 125(5):1028–36.e13Google Scholar
  36. 36.
    Liu T, Kanaoka Y, Barrett NA, Feng C, Garofalo D, Lai J, Buchheit K, Bhattacharya N, Laidlaw TM, Katz HR, Boyce JA (2015) Aspirin-exacerbated respiratory disease involves a cysteinyl leukotriene-driven IL-33-mediated mast cell activation pathway. J Immunol 195(8):3537–3545Google Scholar
  37. 37.
    Buchheit KM, Cahill KN, Katz HR, Murphy KC, Feng C, Lee-Sarwar K, Lai J, Bhattacharyya N, Israel E, Boyce JA, Laidlaw TM (2016) Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 137(5):1566–76.e5Google Scholar
  38. 38.
    Lluis A, Schedel M, Liu J, Illi S, Depner M, von Mutius E, Kabesch M, Schaub B (2011) Asthma-associated polymorphisms in 17q21 influence cord blood ORMDL3 and GSDMA gene expression and IL-17 secretion. J Allergy Clin Immunol 127(6):1587–94.e6Google Scholar
  39. 39.
    Castillo JR, Peters SP, Busse WW (2017) Asthma exacerbations: pathogenesis, prevention, and treatment. J Allergy Clin Immunol Pract 5(4):918–927Google Scholar
  40. 40.
    Edwards MR, Strong K, Cameron A, Walton RP, Jackson DJ, Johnston SL (2017) Viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness. J Allergy Clin Immunol 140(4):909–920Google Scholar
  41. 41.
    Guarnieri M, Balmes JR (2014) Outdoor air pollution and asthma. Lancet 383(9928):1581–1592Google Scholar
  42. 42.
    Undem BJ, Taylor-Clark T (2014) Mechanisms underlying the neuronal-based symptoms of allergy. J Allergy Clin Immunol 133(6):1521–1534Google Scholar
  43. 43.
    Colsoul B, Nilius B, Vennekens R (2009) On the putative role of transient receptor potential cation channels in asthma. Clin Exp Allergy 39(10):1456–1466Google Scholar
  44. 44.
    Bertin S, Aoki-Nonaka Y, de Jong PR, Nohara LL, Xu H, Stanwood SR, Srikanth S, Lee J, To K, Abramson L, Yu T, Han T, Touma R, Li X, González-Navajas JM, Herdman S, Corr M, Fu G, Dong H, Gwack Y, Franco A, Jefferies WA, Raz E (2014) The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4(+) T cells. Nat Immunol 15(11):1055–1063Google Scholar
  45. 45.
    Hahn C, Islamian AP, Renz H, Nockher WA (2006) Airway epithelial cells produce neurotrophins and promote the survival of eosinophils during allergic airway inflammation. J Allergy Clin Immunol 117(4):787–794Google Scholar
  46. 46.
    Biomarkers Definitions Working G (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95Google Scholar
  47. 47.
    Hastie AT, Moore WC, Li H, Rector BM, Ortega VE, Pascual RM, Peters SP, Meyers DA, Bleecker ER, National Heart, Lung, and Blood Institute's Severe Asthma Research Program (2013) Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol 132(1):72–80Google Scholar
  48. 48.
    Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH et al (2015) External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 70(2):115–120Google Scholar
  49. 49.
    Fitzpatrick AM, Jackson DJ, Mauger DT, Boehmer SJ, Phipatanakul W, Sheehan WJ, Moy JN, Paul IM, Bacharier LB, Cabana MD, Covar R, Holguin F, Lemanske RF Jr, Martinez FD, Pongracic JA, Beigelman A, Baxi SN, Benson M, Blake K, Chmiel JF, Daines CL, Daines MO, Gaffin JM, Gentile DA, Gower WA, Israel E, Kumar HV, Lang JE, Lazarus SC, Lima JJ, Ly N, Marbin J, Morgan W, Myers RE, Olin JT, Peters SP, Raissy HH, Robison RG, Ross K, Sorkness CA, Thyne SM, Szefler SJ, NIH/NHLBI AsthmaNet (2016) Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 138(6):1608–18.e12Google Scholar
  50. 50.
    Nair P, O'Byrne PM (2016) Measuring eosinophils to make treatment decisions in asthma. Chest 150(3):485–487Google Scholar
  51. 51.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E et al (2009) Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 360(10):985–993Google Scholar
  52. 52.
    Burrows B, Martinez FD, Cline MG, Lebowitz MD (1995) The relationship between parental and children's serum IgE and asthma. Am J Respir Crit Care Med 152(5 Pt 1):1497–1500Google Scholar
  53. 53.
    Gerald JK, Gerald LB, Vasquez MM, Morgan WJ, Boehmer SJ, Lemanske RF Jr, Mauger DT, Strunk RC, Szefler SJ, Zeiger RS, Bacharier LB, Bade E, Covar RA, Guilbert TW, Heidarian-Raissy H, Kelly HW, Malka-Rais J, Sorkness CA, Taussig LM, Chinchilli VM, Martinez FD (2015) Markers of differential response to inhaled corticosteroid treatment among children with mild persistent asthma. J Allergy Clin Immunol Pract 3(4):540–6.e3Google Scholar
  54. 54.
    Pillai P, Chan YC, Wu SY, Ohm-Laursen L, Thomas C, Durham SR, Menzies-Gow A, Rajakulasingam RK, Ying S, Gould HJ, Corrigan CJ (2016) Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J 48(6):1593–1601Google Scholar
  55. 55.
    Szefler SJ, Wenzel S, Brown R, Erzurum SC, Fahy JV, Hamilton RG, Hunt JF, Kita H, Liu AH, Panettieri RA Jr, Schleimer RP, Minnicozzi M (2012) Asthma outcomes: biomarkers. J Allergy Clin Immunol 129(3 Suppl):S9–S23Google Scholar
  56. 56.
    Lim HF, Nair P (2018) Airway inflammation and inflammatory biomarkers. Semin Respir Crit Care Med 39(1):56–63Google Scholar
  57. 57.
    Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, Carter R, Audusseau S, Hamid Q, Bradding P, Fahy JV, Woodruff PG, Harris JM, Arron JR, Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group (2012) Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 130(3):647–54.e10Google Scholar
  58. 58.
    Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR et al (2011) Lebrikizumab treatment in adults with asthma. N Engl J Med 365(12):1088–1098Google Scholar
  59. 59.
    Shiobara T, Chibana K, Watanabe T, Arai R, Horigane Y, Nakamura Y, Hayashi Y, Shimizu Y, Takemasa A, Ishii Y (2016) Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells. Respir Res 17:28Google Scholar
  60. 60.
    Divekar R, Hagan J, Rank M, Park M, Volcheck G, O'Brien E, Meeusen J, Kita H, Butterfield J (2016) Diagnostic utility of urinary LTE4 in asthma, allergic rhinitis, chronic rhinosinusitis, nasal polyps, and aspirin sensitivity. J Allergy Clin Immunol Pract 4(4):665–670Google Scholar
  61. 61.
    Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Arron JR, Koth LL, Fahy JV (2009) T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180(5):388–395Google Scholar
  62. 62.
    Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, Hoda U, Rossios C, Sousa A, Wilson SJ, Howarth P, Dahlen B, Dahlen SE, Chanez P, Shaw D, Krug N, Sandstrӧm T, de Meulder B, Lefaudeux D, Fowler S, Fleming L, Corfield J, Auffray C, Sterk PJ, Djukanovic R, Guo Y, Adcock IM, Chung KF, U-BIOPRED Project Team ‡ (2017) A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED. Am J Respir Crit Care Med 195(4):443–455Google Scholar
  63. 63.
    Carr TF, Kraft M (2016) Chronic infection and severe asthma. Immunol Allergy Clin N Am 36(3):483–502Google Scholar
  64. 64.
    Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG (2014) Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J 43(4):1067–1076Google Scholar
  65. 65.
    Marwick JA, Dorward DA, Lucas CD, Jones KO, Sheldrake TA, Fox S, Ward C, Murray J, Brittan M, Hirani N, Duffin R, Dransfield I, Haslett C, Rossi AG (2013) Oxygen levels determine the ability of glucocorticoids to influence neutrophil survival in inflammatory environments. J Leukoc Biol 94(6):1285–1292Google Scholar
  66. 66.
    Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J, Trudeau J, Huff R, Pilewski J, Holguin F, Kolls J, Wenzel S, Ray P, Ray A (2015) High IFN-gamma and low SLPI mark severe asthma in mice and humans. J Clin Invest 125(8):3037–3050Google Scholar
  67. 67.
    Gauthier M, Chakraborty K, Oriss TB, Raundhal M, Das S, Chen J, et al. Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias. JCI Insight. 2017;2(13)Google Scholar
  68. 68.
    Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C et al (2009) T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 123(5):1185–1187Google Scholar
  69. 69.
    Ricciardolo FLM, Sorbello V, Folino A, Gallo F, Massaglia GM, Favata G et al (2017) Identification of IL-17F/frequent exacerbator endotype in asthma. J Allergy Clin Immunol 140(2):395–406Google Scholar
  70. 70.
    McGarvey LP, Butler CA, Stokesberry S, Polley L, McQuaid S, Abdullah H et al (2014) Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. J Allergy Clin Immunol 133(3):704–12.e4Google Scholar
  71. 71.
    Peters U, Dixon AE, Forno E (2018) Obesity and asthma. J Allergy Clin Immunol 141(4):1169–1179Google Scholar
  72. 72.
    Rastogi D, Fraser S, Oh J, Huber AM, Schulman Y, Bhagtani RH, Khan ZS, Tesfa L, Hall CB, Macian F (2015) Inflammation, metabolic dysregulation, and pulmonary function among obese urban adolescents with asthma. Am J Respir Crit Care Med 191(2):149–160Google Scholar
  73. 73.
    Takahashi K, Pavlidis S, Ng Kee Kwong F, Hoda U, Rossios C, Sun K, et al. Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis. Eur Respir J. 2018;51(5)Google Scholar
  74. 74.
    Tripple JW, McCracken JL, Calhoun WJ (2017) Biologic therapy in chronic obstructive pulmonary disease. Immunol Allergy Clin N Am 37(2):345–355Google Scholar
  75. 75.
    Pite H, Pereira AM, Morais-Almeida M, Nunes C, Bousquet J, Fonseca JA (2014) Prevalence of asthma and its association with rhinitis in the elderly. Respir Med 108(8):1117–1126Google Scholar
  76. 76.
    Gibson PG, McDonald VM, Marks GB (2010) Asthma in older adults. Lancet 376(9743):803–813Google Scholar
  77. 77.
    Dunn RM, Busse PJ, Wechsler ME (2018) Asthma in the elderly and late-onset adult asthma. Allergy 73(2):284–294Google Scholar
  78. 78.
    Nyenhuis SM, Schwantes EA, Evans MD, Mathur SK (2010) Airway neutrophil inflammatory phenotype in older subjects with asthma. J Allergy Clin Immunol 125(5):1163–1165Google Scholar
  79. 79.
    Schmitt V, Rink L, Uciechowski P (2013) The Th17/Treg balance is disturbed during aging. Exp Gerontol 48(12):1379–1386Google Scholar
  80. 80.
    Maes T, Cobos FA, Schleich F, Sorbello V, Henket M, De Preter K et al (2016) Asthma inflammatory phenotypes show differential microRNA expression in sputum. J Allergy Clin Immunol 137(5):1433–1446Google Scholar
  81. 81.
    Grzela K, Litwiniuk M, Zagorska W, Grzela T (2016) Airway remodeling in chronic obstructive pulmonary disease and asthma: the role of matrix metalloproteinase-9. Arch Immunol Ther Exp (Warsz) 64(1):47–55Google Scholar
  82. 82.
    Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV, National Heart, Lung, and Blood Institute Severe Asthma Research Program (2016) Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med 4(7):574–584Google Scholar
  83. 83.
    Krug N, Madden J, Redington AE, Lackie P, Djukanovic R, Schauer U, Holgate ST, Frew AJ, Howarth PH (1996) T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol 14(4):319–326Google Scholar
  84. 84.
    Modena BD, Tedrow JR, Milosevic J, Bleecker ER, Meyers DA, Wu W, Bar-Joseph Z, Erzurum SC, Gaston BM, Busse WW, Jarjour NN, Kaminski N, Wenzel SE (2014) Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways. Am J Respir Crit Care Med 190(12):1363–1372Google Scholar
  85. 85.
    Wang YH, Voo KS, Liu B, Chen CY, Uygungil B, Spoede W, Bernstein JA, Huston DP, Liu YJ (2010) A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 207(11):2479–2491Google Scholar
  86. 86.
    Li BWS, Stadhouders R, de Bruijn MJW, Lukkes M, Beerens D, Brem MD et al (2017) Group 2 innate lymphoid cells exhibit a dynamic phenotype in allergic airway inflammation. Front Immunol 8:1684Google Scholar
  87. 87.
    Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H, Sly PD (2015) Asthma. Nat Rev Dis Primers 1:15025Google Scholar
  88. 88.
    Bigler J, Boedigheimer M, Schofield JPR, Skipp PJ, Corfield J, Rowe A, Sousa AR, Timour M, Twehues L, Hu X, Roberts G, Welcher AA, Yu W, Lefaudeux D, Meulder B, Auffray C, Chung KF, Adcock IM, Sterk PJ, Djukanović R, U-BIOPRED Study Group ‖ (2017) A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts. Am J Respir Crit Care Med 195(10):1311–1320Google Scholar
  89. 89.
    Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F et al (2017) U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol 139(6):1797–1807Google Scholar
  90. 90.
    Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV (2014) Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol 133(2):388–394Google Scholar
  91. 91.
    Reinke SN, Gallart-Ayala H, Gomez C, Checa A, Fauland A, Naz S, et al. Metabolomics analysis identifies different metabotypes of asthma severity. Eur Respir J. 2017;49(3)Google Scholar
  92. 92.
    Rufo JC, Madureira J, Fernandes EO, Moreira A (2016) Volatile organic compounds in asthma diagnosis: a systematic review and meta-analysis. Allergy 71(2):175–188Google Scholar
  93. 93.
    Maniscalco M, Paris D, Melck DJ, D'Amato M, Zedda A, Sofia M, Stellato C, Motta A (2017) Coexistence of obesity and asthma determines a distinct respiratory metabolic phenotype. J Allergy Clin Immunol 139(5):1536–47.e5Google Scholar
  94. 94.
    Park YH, Fitzpatrick AM, Medriano CA, Jones DP (2017) High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children. J Allergy Clin Immunol 139(5):1518–24.e4Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of MedicineEmory UniversityAtlantaUSA
  2. 2.Division of Pulmonary, Allergy & Immunology, Cystic Fibrosis, and Sleep, Department of PediatricsEmory UniversityAtlantaUSA
  3. 3.Lowance Center for Human ImmunologyEmory UniversityAtlantaUSA

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