Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Asthma phenotypes: the evolution from clinical to molecular approaches

Abstract

Although asthma has been considered as a single disease for years, recent studies have increasingly focused on its heterogeneity. The characterization of this heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link biology to phenotype, often through a statistically based process. Ongoing studies of large-scale, molecularly and genetically focused and extensively clinically characterized cohorts of asthma should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to asthma therapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the umbrella term 'asthma'.
Figure 2: TH2 immune processes in the airways of people with asthma.
Figure 3: Theoretical grouping of emerging asthma phenotypes based on the distinction between TH2-high asthma and non-TH2 asthma.
Figure 4: Theoretical range of factors that may be involved in the development of non-TH2 asthma.

Similar content being viewed by others

References

  1. A plea to abandon asthma as a disease concept. Lancet 368, 705 (2006).

  2. Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    CAS  Google Scholar 

  3. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    CAS  Google Scholar 

  4. Zhang, D.H. et al. Inhibition of allergic inflammation in a murine model of asthma by expression of a dominant-negative mutant of GATA-3. Immunity 11, 473–482 (1999).

    CAS  Google Scholar 

  5. Flood-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).

    CAS  Google Scholar 

  6. Borish, L.C. et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160, 1816–1823 (1999).

    CAS  Google Scholar 

  7. Leckie, M.J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).

    CAS  Google Scholar 

  8. Wenzel, S.E. 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. 160, 1001–1008 (1999).

    CAS  Google Scholar 

  9. Green, R.H. et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360, 1715–1721 (2002).

    Google Scholar 

  10. Green, R.H. et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57, 875–879 (2002).

    CAS  Google Scholar 

  11. Jayaram, L. et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J. 27, 483–494 (2006).

    CAS  Google Scholar 

  12. Solèr, M. et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J. 18, 254–261 (2001).

    Google Scholar 

  13. Busse, W. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 108, 184–190 (2001).

    CAS  Google Scholar 

  14. Rackemann, F. A working classification of asthma. Am. J. Med. 3, 601–606 (1947).

    CAS  Google Scholar 

  15. Samter, M. & Beers, R.F. Jr. Concerning the nature of intolerance to aspirin. J. Allergy 40, 281–293 (1967).

    CAS  Google Scholar 

  16. Merriam-Webster's Collegiate Dictionary 11th edn (Merriam-Webster, Inc., 2008).

  17. Anderson, G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1119 (2008).

    Google Scholar 

  18. Lötvall, J. et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J. Allergy Clin. Immunol. 127, 355–360 (2011).

    Google Scholar 

  19. Wenzel, S.E. Asthma: defining of the persistent adult phenotypes. Lancet 368, 804–813 (2006).

    CAS  Google Scholar 

  20. Humbert, M. et al. IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am. J. Respir. Crit. Care Med. 154, 1497–1504 (1996).

    CAS  Google Scholar 

  21. Humbert, M. et al. High-affinity IgE receptor (FcɛRI)-bearing cells in bronchial biopsies from atopic and nonatopic asthma. Am. J. Respir. Crit. Care Med. 153, 1931–1937 (1996).

    CAS  Google Scholar 

  22. National Heart, Lung, and Blood Institutes. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (NIH Publication No. 07-4051) (US Department of Health and Human Services, Bethesda, 2007).

  23. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention 2011. Global Initiative for Asthma <http://www.ginasthma.org/guidelines-gina-report-global-strategy-for-asthma.html> Ch. 7, 93–132 (2008).

  24. Wenzel, S.E. et al. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med. 156, 737–743 (1997).

    CAS  Google Scholar 

  25. Miranda, C., Busacker, A., Balzar, S., Trudeau, J. & Wenzel, S.E. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J. Allergy Clin. Immunol. 113, 101–108 (2004).

    Google Scholar 

  26. Pizzichini, M.M. et al. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur. Respir. J. 13, 15–21 (1999).

    CAS  Google Scholar 

  27. Gibson, P.G., Simpson, J.L., Hankin, R., Powell, H. & Henry, R.L. Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax 58, 116–121 (2003).

    CAS  Google Scholar 

  28. Haldar, P. et al. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 178, 218–224 (2008).

    Google Scholar 

  29. Moore, W.C. et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am. J. Respir. Crit. Care Med. 181, 315–323 (2010).

    Google Scholar 

  30. Siroux, V. et al. Identifying adult asthma phenotypes using a clustering approach. Eur. Respir. J. 38, 310–317 (2011).

    CAS  Google Scholar 

  31. Fitzpatrick, A.M. 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. 127, 382–389.e13 (2011).

    Google Scholar 

  32. Chibana, K. et al. IL-13–induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clin. Exp. Allergy 38, 936–946 (2008).

    CAS  Google Scholar 

  33. Dweik, R.A. et al. An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FeNO) for Clinical Applications. Am. J. Respir. Crit. Care Med. 184, 602–615 (2011).

    CAS  Google Scholar 

  34. Fei, M. et al. TNF-α from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection. Proc. Natl. Acad. Sci. USA 108, 5360–5365 (2011).

    CAS  Google Scholar 

  35. Woodruff, P.G. et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 (2009).

    CAS  Google Scholar 

  36. Dougherty, R.H. et al. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma. J. Allergy Clin. Immunol. 125, 1046–1053.e8 (2010).

    CAS  Google Scholar 

  37. Hallstrand, T.S., Moody, M.W., Aitken, M.L. & Henderson, W.R. Jr. Airway immunopathology of asthma with exercise-induced bronchoconstriction. J. Allergy Clin. Immunol. 116, 586–593 (2005).

    CAS  Google Scholar 

  38. Hallstrand, T.S. et al. Inflammatory basis of exercise-induced bronchoconstriction. Am. J. Respir. Crit. Care Med. 172, 679–686 (2005).

    Google Scholar 

  39. Hallstrand, T.S. et al. Transglutaminase 2, a novel regulator of eicosanoid production in asthma revealed by genome-wide expression profiling of distinct asthma phenotypes. PLoS ONE 5, e8583 (2010).

    Google Scholar 

  40. Szefler, S.J. et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J. Allergy Clin. Immunol. 115, 233–242 (2005).

    CAS  Google Scholar 

  41. Pearce, N., Douwes, J. & Beasley, R. Is allergen exposure the major primary cause of asthma? Thorax 55, 424–431 (2000).

    CAS  Google Scholar 

  42. Phelan, P.D., Robertson, C.F. & Olinsky, A. The Melbourne Asthma Study: 1964–1999. J. Allergy Clin. Immunol. 109, 189–194 (2002).

    Google Scholar 

  43. Gamble, C. et al. Racial differences in biologic predictors of severe asthma: data from the Severe Asthma Research Program. J. Allergy Clin. Immunol. 126, 1149–1156.e1 (2010).

    Google Scholar 

  44. Lajoie, S. et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat. Immunol. 11, 928–935 (2010).

    CAS  Google Scholar 

  45. McKinley, L. et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 181, 4089–4097 (2008).

    CAS  Google Scholar 

  46. Murdock, B.J. et al. Coevolution of TH1, TH2, and TH17 responses during repeated pulmonary exposure to Aspergillus fumigatus conidia. Infect. Immun. 79, 125–135 (2011).

    CAS  Google Scholar 

  47. Moffatt, M.F. et al. A large-scale, consortium-based genome-wide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    CAS  Google Scholar 

  48. Bisgaard, H. et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am. J. Respir. Crit. Care Med. 179, 179–185 (2009).

    CAS  Google Scholar 

  49. Slager, R.E. et al. Predictive model of severe atopic asthma phenotypes using interleukin-4/13 pathway polymorphisms. Am. J. Respir. Crit. Care Med. 183, A1332 (2011).

    Google Scholar 

  50. Wu, C.Y., Fargeas, C., Nakajima, T. & Delespesse, G. Glucocorticoids suppress the production of interleukin-4 by human lymphocytes. Eur. J. Immunol. 21, 2645–2647 (1991).

    CAS  Google Scholar 

  51. Kunicka, J.E. et al. Immunosuppression by glucocorticoids: inhibition of production of multiple lymphokines by in vivo administration of dexamethasone. Cell. Immunol. 149, 39–49 (1993).

    CAS  Google Scholar 

  52. Maneechotesuwan, K. et al. Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease. PLoS Med. 6, e1000076 (2009).

    Google Scholar 

  53. Berry, M. et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 62, 1043–1049 (2007).

    Google Scholar 

  54. Djukanović, R. et al. Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am. Rev. Respir. Dis. 142, 863–871 (1990).

    Google Scholar 

  55. Djukanović, R. et al. The effect of treatment with oral corticosteroids on asthma symptoms and airway inflammation. Am. J. Respir. Crit. Care Med. 155, 826–832 (1997).

    Google Scholar 

  56. Fahy, J.V. et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am. J. Respir. Crit. Care Med. 155, 1828–1834 (1997).

    CAS  Google Scholar 

  57. Gauvreau, G.M. et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am. J. Respir. Crit. Care Med. 183, 1007–1014 (2011).

    CAS  Google Scholar 

  58. Wenzel, S., Wilbraham, D., Fuller, R., Getz, E.B. & 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 370, 1422–1431 (2007).

    CAS  Google Scholar 

  59. Slager, R.E. et al. IL-4 receptor α polymorphisms are predictors of a pharmacogenetic response to a novel IL-4/IL-13 antagonist. J. Allergy Clin. Immunol. 126, 875–878 (2010).

    CAS  Google Scholar 

  60. Hanania, N.A. et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med. 154, 573–582 (2011).

    Google Scholar 

  61. Humbert, M., Berger, W., Rapatz, G. & Turk, F. Add-on omalizumab improves day-to-day symptoms in inadequately controlled severe persistent allergic asthma. Allergy 63, 592–596 (2008).

    CAS  Google Scholar 

  62. Busse, W.W. et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N. Engl. J. Med. 364, 1005–1015 (2011).

    CAS  Google Scholar 

  63. Fitzpatrick, A.M., Gaston, B.M., Erzurum, S.C. & Teague, W.G. Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide. J. Allergy Clin. Immunol. 118, 1218–1225 (2006).

    CAS  Google Scholar 

  64. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).

    CAS  Google Scholar 

  65. Arron, J. et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 183, A4455 (2011).

    Google Scholar 

  66. Scheerens, H. et al. Predictive and pharmacodynamic biomarkers of interleukin-13 blockade: effect of lebrikizumab on late-phase asthmatic response to allergen challenge. J. Allergy Clin. Immunol. 127, AB164 (2011).

    Google Scholar 

  67. Saha, S.K. et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J. Allergy Clin. Immunol. 121, 685–691 (2008).

    CAS  Google Scholar 

  68. Chibana, K. et al. Balance of inducible nitric oxide synthase and arginase 2 in bronchial epithelial cells from asthmatic subjects predicts asthma severity: Symptoms and inflammatory processes. Am. J. Respir. Crit. Care Med. 177, A975 (2008).

    Google Scholar 

  69. Kharitonov, S.A. & Barnes, P.J. Nitric oxide in exhaled air is a new marker of airway inflammation. Monaldi Arch. Chest Dis. 51, 533–537 (1996).

    CAS  Google Scholar 

  70. Belda, J. et al. Induced sputum cell counts in healthy adults. Am. J. Respir. Crit. Care Med. 161, 475–478 (2000).

    CAS  Google Scholar 

  71. Spanevello, A. et al. Induced sputum cellularity. Reference values and distribution in normal volunteers. Am. J. Respir. Crit. Care Med. 162, 1172–1174 (2000).

    CAS  Google Scholar 

  72. van Veen, I.H. et al. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J. Allergy Clin. Immunol. 124, 615–617.e2 (2009).

    Google Scholar 

  73. Heller, F. et al. Interleukin-13 is the key effector TH2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

    CAS  Google Scholar 

  74. Hoshino, T. et al. Pulmonary inflammation and emphysema: role of the cytokines IL-18 and IL-13. Am. J. Respir. Crit. Care Med. 176, 49–62 (2007).

    CAS  Google Scholar 

  75. Tepper, R.I., Coffman, R.L. & Leder, P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science 257, 548–551 (1992).

    CAS  Google Scholar 

  76. Hastie, A.T. et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J. Allergy Clin. Immunol. 125, 1028–1036.e13 (2010).

    CAS  Google Scholar 

  77. Eiwegger, T. & Akdis, C.A. IL-33 links tissue cells, dendritic cells and TH2 cell development in a mouse model of asthma. Eur. J. Immunol. 41, 1535–1538 (2011).

    CAS  Google Scholar 

  78. Doe, C. et al. Expression of the T helper 17–associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 138, 1140–1147 (2010).

    CAS  Google Scholar 

  79. Shannon, J. et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 133, 420–426 (2008).

    CAS  Google Scholar 

  80. Cowburn, A.S. et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin. Invest. 101, 834–846 (1998).

    CAS  Google Scholar 

  81. Christie, P.E. et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am. Rev. Respir. Dis. 143, 1025–1029 (1991).

    CAS  Google Scholar 

  82. Sanak, M., Simon, H.U. & Szczeklik, A. Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 350, 1599–1600 (1997).

    CAS  Google Scholar 

  83. Choi, J.H. et al. Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase. Hum. Genet. 114, 337–344 (2004).

    CAS  Google Scholar 

  84. Bachert, C., Wagenmann, M., Hauser, U. & Rudack, C. IL-5 synthesis is upregulated in human nasal polyp tissue. J. Allergy Clin. Immunol. 99, 837–842 (1997).

    CAS  Google Scholar 

  85. Sánchez-Segura, A., Brieva, J.A. & Rodriguez, C. T lymphocytes that infiltrate nasal polyps have a specialized phenotype and produce a mixed TH1/TH2 pattern of cytokines. J. Allergy Clin. Immunol. 102, 953–960 (1998).

    Google Scholar 

  86. Stankovic, K.M., Goldsztein, H., Reh, D.D., Platt, M.P. & Metson, R. Gene expression profiling of nasal polyps associated with chronic sinusitis and aspirin-sensitive asthma. Laryngoscope 118, 881–889 (2008).

    CAS  Google Scholar 

  87. Chu, H.W. et al. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition. Clin. Exp. Allergy 32, 1558–1565 (2002).

    CAS  Google Scholar 

  88. Yamamoto, M. et al. Nitric oxide and related enzymes in asthma: Relation to severity, enzyme function and inflammation. Clin. Exp. Allergy doi: 10.1111/j.1365-2222.2011.03860.x (2011).

  89. Stirling, R.G. et al. Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group. Thorax 53, 1030–1034 (1998).

    CAS  Google Scholar 

  90. Haldar, P. et al. Mepolizumab (anti–IL-5) and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009).

    CAS  Google Scholar 

  91. Schleimer, R.P. & Bochner, B.S. The effects of glucocorticoids on human eosinophils. J. Allergy Clin. Immunol. 94, 1202–1213 (1994).

    CAS  Google Scholar 

  92. Woolley, K.L. et al. Eosinophil apoptosis and the resolution of airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 154, 237–243 (1996).

    CAS  Google Scholar 

  93. ten Brinke, A., Zwinderman, A.H., Sterk, P.J., Rabe, K.F. & Bel, E.H. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am. J. Respir. Crit. Care Med. 170, 601–605 (2004).

    Google Scholar 

  94. Dahlén, B. et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am. J. Respir. Crit. Care Med. 157, 1187–1194 (1998).

    Google Scholar 

  95. Dahlén, S.E. et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 165, 9–14 (2002).

    Google Scholar 

  96. Nair, P. et al. Mepolizumab in prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).

    CAS  Google Scholar 

  97. Wenzel, S. et al. A phase 2b study of inhaled pitrakinra, an IL-4/IL-13 antagonist, successfully identified responder subpopulations of patients with uncontrolled asthma. Am. J. Respir. Crit. Care Med. 183, A19045 (2011).

    Google Scholar 

  98. Helenius, I.J., Tikkanen, H.O., Sarna, S. & Haahtela, T. Asthma and increased bronchial responsiveness in elite athletes: atopy and sport event as risk factors. J. Allergy Clin. Immunol. 101, 646–652 (1998).

    CAS  Google Scholar 

  99. Karjalainen, E.M. et al. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am. J. Respir. Crit. Care Med. 161, 2086–2091 (2000).

    CAS  Google Scholar 

  100. Finnerty, J.P., Wood-Baker, R., Thomson, H. & Holgate, S.T. Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204219, a potent leukotriene D4 receptor antagonist. Am. Rev. Respir. Dis. 145, 746–749 (1992).

    CAS  Google Scholar 

  101. Reiss, T.F. et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax 52, 1030–1035 (1997).

    CAS  Google Scholar 

  102. Parker, J.M. et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti–interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm. Med. 11, 14 (2011).

    CAS  Google Scholar 

  103. Bisgaard, H. & Bønnelykke, K. Long-term studies of the natural history of asthma in childhood. J. Allergy Clin. Immunol. 126, 187–197 (2010).

    Google Scholar 

  104. Martin, P.E. et al. Childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: a prospective cohort study over 4 decades. J. Allergy Clin. Immunol. 127, 1473–1479.e1 (2011).

    Google Scholar 

  105. Corren, J. et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Rα antagonist, in patients with asthma. Am. J. Respir. Crit. Care Med. 181, 788–796 (2010).

    CAS  Google Scholar 

  106. Kim, H.Y., DeKruyff, R.H. & Umetsu, D.T. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat. Immunol. 11, 577–584 (2010).

    CAS  Google Scholar 

  107. Black, J.L. & Roth, M. Intrinsic asthma: is it intrinsic to the smooth muscle? Clin. Exp. Allergy 39, 962–965 (2009).

    CAS  Google Scholar 

  108. Li, X. et al. Importance of hedgehog interacting protein and other lung function genes in asthma. J. Allergy Clin. Immunol. 127, 1457–1465 (2011).

    CAS  Google Scholar 

  109. van Diemen, C.C. et al. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am. J. Respir. Crit. Care Med. 172, 329–333 (2005).

    Google Scholar 

  110. Brightling, C.E. et al. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am. J. Respir. Crit. Care Med. 171, 1103–1108 (2005).

    Google Scholar 

  111. Yu, M. et al. Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J. Clin. Invest. 121, 3133–3143 (2011).

    CAS  Google Scholar 

  112. Locke, G.R. III, Talley, N.J., Fett, S.L., Zinsmeister, A.R. & Melton, L.J. III Risk factors associated with symptoms of gastroesophageal reflux. Am. J. Med. 106, 642–649 (1999).

    Google Scholar 

  113. Nilsson, M., Johnsen, R., Ye, W., Hveem, K. & Lagergren, J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms. J. Am. Med. Assoc. 290, 66–72 (2003).

    CAS  Google Scholar 

  114. Sin, D.D., Jones, R.L. & Man, S.F. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch. Intern. Med. 162, 1477–1481 (2002).

    Google Scholar 

  115. Pakhale, S. et al. A comparison of obese and nonobese people with asthma: exploring an asthma-obesity interaction. Chest 137, 1316–1323 (2010).

    Google Scholar 

  116. Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    CAS  Google Scholar 

  117. Loffreda, S. et al. Leptin regulates proinflammatory immune responses. FASEB J. 12, 57–65 (1998).

    CAS  Google Scholar 

  118. Komakula, S. et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir. Res. 8, 32 (2007).

    Google Scholar 

  119. Peters-Golden, M. et al. Influence of body mass index on the response to asthma controller agents. Eur. Respir. J. 27, 495–503 (2006).

    CAS  Google Scholar 

  120. Dixon, A.E. et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J. Allergy Clin. Immunol. 128, 508–515.e2 (2011).

    Google Scholar 

  121. Holguin, F. et al. Obesity and asthma: an association modified by age of asthma onset. J. Allergy Clin. Immunol. 127, 1486–1493.e2 (2011).

    Google Scholar 

  122. Reddy, R.C., Baptist, A.P., Fan, Z., Carlin, A.M. & Birkmeyer, N.J. The effects of bariatric surgery on asthma severity. Obes. Surg. 21, 200–206 (2011).

    Google Scholar 

  123. Lugogo, N.L., Kraft, M. & Dixon, A.E. Does obesity produce a distinct asthma phenotype? J. Appl. Physiol. 108, 729–734 (2010).

    Google Scholar 

  124. Jatakanon, A. et al. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med. 160, 1532–1539 (1999).

    CAS  Google Scholar 

  125. Schleimer, R.P., Freeland, H.S., Peters, S.P., Brown, K.E. & Derse, C.P. An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. J. Pharmacol. Exp. Ther. 250, 598–605 (1989).

    CAS  Google Scholar 

  126. Kato, T., Takeda, Y., Nakada, T. & Sendo, F. Inhibition by dexamethasone of human neutrophil apoptosis in vitro. Nat. Immun. 14, 198–208 (1995).

    CAS  Google Scholar 

  127. Woodruff, P.G. et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J. Allergy Clin. Immunol. 108, 753–758 (2001).

    CAS  Google Scholar 

  128. Busacker, A. et al. A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest 135, 48–56 (2009).

    Google Scholar 

  129. Gupta, S. et al. Qualitative analysis of high-resolution CT scans in severe asthma. Chest 136, 1521–1528 (2009).

    Google Scholar 

  130. Vignola, A.M. et al. Increased levels of elastase and α1-antitrypsin in sputum of asthmatic patients. Am. J. Respir. Crit. Care Med. 157, 505–511 (1998).

    CAS  Google Scholar 

  131. Simpson, J.L., Scott, R.J., Boyle, M.J. & Gibson, P.G. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am. J. Respir. Crit. Care Med. 172, 559–565 (2005).

    Google Scholar 

  132. Cowan, D.C., Cowan, J.O., Palmay, R., Williamson, A. & Taylor, D.R. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 65, 384–390 (2010).

    Google Scholar 

  133. Baines, K.J., Simpson, J.L., Wood, L.G., Scott, R.J. & Gibson, P.G. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J. Allergy Clin. Immunol. 127, 153–160.e9 (2011).

    CAS  Google Scholar 

  134. Bourgeois, E.A. et al. A natural protective function of invariant NKT cells in a mouse model of innate-cell-driven lung inflammation. Eur. J. Immunol. 41, 299–305 (2011).

    CAS  Google Scholar 

  135. Simpson, J.L., Powell, H., Boyle, M.J., Scott, R.J. & Gibson, P.G. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am. J. Respir. Crit. Care Med. 177, 148–155 (2008).

    CAS  Google Scholar 

  136. Wenzel, S.E. et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009).

    CAS  Google Scholar 

  137. Chakir, J. et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression. J. Allergy Clin. Immunol. 111, 1293–1298 (2003).

    CAS  Google Scholar 

  138. Holt, P.G. & Sly, P.D. Interaction between adaptive and innate immune pathways in the pathogenesis of atopic asthma: operation of a lung/bone marrow axis. Chest 139, 1165–1171 (2011).

    Google Scholar 

  139. Thomson, N.C. & Chaudhuri, R. Asthma in smokers: challenges and opportunities. Curr. Opin. Pulm. Med. 15, 39–45 (2009).

    Google Scholar 

  140. van den Berge, M., Heijink, H.I., van Oosterhout, A.J. & Postma, D.S. The role of female sex hormones in the development and severity of allergic and non-allergic asthma. Clin. Exp. Allergy 39, 1477–1481 (2009).

    CAS  Google Scholar 

  141. Singh, A.M., Moore, P.E., Gern, J.E., Lemanske, R.F. Jr. & Hartert, T.V. Bronchiolitis to asthma: a review and call for studies of gene–virus interactions in asthma causation. Am. J. Respir. Crit. Care Med. 175, 108–119 (2007).

    CAS  Google Scholar 

  142. Gern, J.E. The ABCs of rhinoviruses, wheezing, and asthma. J. Virol. 84, 7418–7426 (2010).

    CAS  Google Scholar 

  143. Maestrelli, P., Boschetto, P., Fabbri, L.M. & Mapp, C.E. Mechanisms of occupational asthma. J. Allergy Clin. Immunol. 123, 531–542 (2009).

    Google Scholar 

Download references

Acknowledgements

The author thanks F. Holguin and P. Woodruff for their thoughtful review of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sally E Wenzel.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wenzel, S. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 18, 716–725 (2012). https://doi.org/10.1038/nm.2678

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2678

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing