Skip to main content

Advertisement

Log in

Biomarkers of Airway Type-2 Inflammation and Integrating Complex Phenotypes to Endotypes in Asthma

Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Over the past decade, the most important advance in the field of asthma has been the widespread recognition that asthma is a heterogeneous disease driven by multiple molecular processes.

Recent Findings

The most well-established molecular mechanism in asthma is increased airway type-2 inflammation, and consequently, non-invasive biomarkers of increased airway type-2 inflammation, such as blood eosinophil counts or blood periostin levels, have proven important in stratifying asthma patients in clinical trials of type-2 cytokine inhibitors. However, it remains ambiguous how well these non-invasive biomarkers represent airway measures of type-2 inflammation in asthma. As a result, the utility of these biomarkers to assist with asthma management or as research tools to better understand asthma pathogenesis remains unclear.

Summary

This article reviews primary data assessing biomarkers of airway type-2 inflammation in asthma and describes how the use of biomarkers can advance a precision medicine approach to asthma treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health. 2012;12:204.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson CA, et al. National surveillance of asthma: United States, 2001-2010. Vital Health Stat Ser 3 Anal Epidemiol Stud US Dept Health Hum Serv Public Health Serv Natl Cent Health Stat. 2012;35:1–58.

    Google Scholar 

  3. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94–138.

    Google Scholar 

  4. 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(2):343–73.

    Article  CAS  PubMed  Google Scholar 

  5. Cloutier MM, Hall CB, Wakefield DB, Bailit H. Use of asthma guidelines by primary care providers to reduce hospitalizations and emergency department visits in poor, minority, urban children. J Pediatr. 2005;146(5):591–7.

    Article  PubMed  Google Scholar 

  6. Higashi A, Zhu S, Stafford RS, Alexander GC. National trends in ambulatory asthma treatment, 1997-2009. J Gen Intern Med. 2011;26(12):1465–70.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Newby C, Heaney LG, Menzies-Gow A, Niven RM, Mansur A, Bucknall C, et al. Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One. 2014;9(7):e102987.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet Lond Engl. 2008;372(9643):1107–19.

    Article  Google Scholar 

  12. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev. 2015;15(1):57–65.

    CAS  Google Scholar 

  13. 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(26):2455–66. In this double-blind, placebo-controlled trial, dupilumab, a monoclonal antibody against interleukin 4 receptor, is associated with a reduced frequency of exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers in patients with moderate-severe asthma and blood or sputum eosinophilia.

    Article  CAS  PubMed  Google Scholar 

  14. 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. The first study to propose that asthma can be broadly divided into Th2-high and Th2-low molecular phenotypes of asthma. It challenged the concept that asthma is exclusively a Type 2 driven inflammatory disease by showing that a gene signature for Type 2-inflammation was present in only half of patients with asthma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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. In this double-blind, placebo-controlled trial, lebrikizumab, a monoclonal antibody to interleukin-13, was associated with a greater improvement in lung function in patients with high pretreatment levels of serum periostin than in patients with low periostin levels.

    Article  CAS  PubMed  Google Scholar 

  16. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56.

    Article  CAS  PubMed  Google Scholar 

  17. Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012;18(5):684–92.

    Article  CAS  PubMed  Google Scholar 

  18. Urban JF, Noben-Trauth N, Donaldson DD, Madden KB, Morris SC, Collins M, et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity. 1998;8(2):255–64.

    Article  CAS  PubMed  Google Scholar 

  19. Gause WC, Wynn TA, Allen JE. Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol. 2013;13(8):607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu D, Molofsky AB, Liang H-E, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332(6026):243–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388–94. This group demonstrated that gene expression of the type-2 cytokines IL-4, IL-5, and IL-13 can be quantified from induced sputum RNA, using qPCR based techniques. This technology allows researchers to endotype large cohorts of asthma subjects as Th2-high and Th2-low and examine the relationships between patient outcomes and measures of type 2 inflammation.

  22. Bhakta NR, Solberg OD, Nguyen CP, Nguyen CN, Arron JR, Fahy JV, et al. A qPCR-based metric of Th2 airway inflammation in asthma. Clin Transl Allergy. 2013;3(1):24–7022 – 3–24.

  23. Rackemann FM. A working classification of asthma. Am J Med. 1947;3(5):601–6.

    Article  CAS  PubMed  Google Scholar 

  24. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989;320(5):271–7.

    Article  CAS  PubMed  Google Scholar 

  25. Ostergaard PA. Non-IgE-mediated asthma in children. Acta Paediatr Scand. 1985;74(5):713–9.

    Article  CAS  PubMed  Google Scholar 

  26. Pène J, Rousset F, Brière F, Chrétien I, Bonnefoy JY, Spits H, et al. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988;85(18):6880–4.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Platts-Mills T a E. The Role of Immunoglobulin E in Allergy and Asthma. Am J Respir Crit Care Med. 2001;164(supplement_1):S1–5.

    Article  CAS  PubMed  Google Scholar 

  28. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108(2):184–90.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mediaty A, Neuber K. Total and specific serum IgE decreases with age in patients with allergic rhinitis, asthma and insect allergy but not in patients with atopic dermatitis. Immun Ageing A. 2005;2:9.

    Article  Google Scholar 

  31. Omenaas E, Bakke P, Elsayed S, Hanoa R, Gulsvik A. Total and specific serum IgE levels in adults: relationship to sex, age and environmental factors. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 1994;24(6):530–9.

    Article  CAS  Google Scholar 

  32. Bousquet J, Wenzel S, Holgate S, Lumry W, Freeman P, Fox H. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest. 2004;125(4):1378–86.

    Article  CAS  PubMed  Google Scholar 

  33. Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med. 2007;101(7):1483–92.

    Article  CAS  PubMed  Google Scholar 

  34. 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):647–54.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Naqvi M, Choudhry S, Tsai H-J, Thyne S, Navarro D, Nazario S, et al. Association between IgE levels and asthma severity among African American, Mexican, and Puerto Rican patients with asthma. J Allergy Clin Immunol. 2007;120(1):137–43.

    Article  CAS  PubMed  Google Scholar 

  36. Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323(15):1033–9.

    Article  CAS  PubMed  Google Scholar 

  37. Gershman NH, Wong HH, Liu JT, Mahlmeister MJ, Fahy JV. Comparison of two methods of collecting induced sputum in asthmatic subjects. Eur Respir J. 1996;9(12):2448–53.

    Article  CAS  PubMed  Google Scholar 

  38. Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax. 1992;47(1):25–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med. 2001;164(5):744–8.

    Article  PubMed  Google Scholar 

  40. 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 Lond Engl. 2002;360(9347):1715–21.

    Article  Google Scholar 

  41. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Godon P, Boulet LP, Malo JL, Cartier A, Lemière C. Assessment and evaluation of symptomatic steroid-naive asthmatics without sputum eosinophilia and their response to inhaled corticosteroids. Eur Respir J. 2002;20(6):1364–9.

    Article  CAS  PubMed  Google Scholar 

  43. Arron JR, Izuhara K. Asthma biomarkers: what constitutes a “gold standard”? Thorax. 2015;70(2):105–7.

    Article  PubMed  Google Scholar 

  44. Peters SP. Counterpoint: Is measuring sputum eosinophils useful in the management of severe asthma? No, not for the vast majority of patients. Chest. 2011;139(6):1273–5. discussion 1275–8.

    Article  PubMed  Google Scholar 

  45. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67(3):199–208.

    Article  CAS  PubMed  Google Scholar 

  46. Moncada S, Palmer RM, Higgs EA. Biosynthesis of nitric oxide from l-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989;38(11):1709–15.

    Article  CAS  PubMed  Google Scholar 

  47. Meurs H, Maarsingh H, Zaagsma J. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci. 2003;24(9):450–5.

    Article  CAS  PubMed  Google Scholar 

  48. Korevaar DA, Westerhof GA, Wang J, Cohen JF, Spijker R, Sterk PJ, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med. 2015;3(4):290–300. This systematic review and meta-analysis addresses the diagnostic accuracy of markers of airway eosinophilia (FeNO, blood eosinophils and total IgE) against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy. It shows that their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives.

    Article  PubMed  Google Scholar 

  49. Jacinto T, Alving K, Correia R, Costa-Pereira A, Fonseca J. Setting reference values for exhaled nitric oxide: a systematic review. Clin Respir J. 2013;7(2):113–20.

    Article  CAS  PubMed  Google Scholar 

  50. Singleton MD, Sanderson WT, Mannino DM. Body mass index, asthma and exhaled nitric oxide in U.S. adults, 2007-2010. J Asthma Off J Assoc Care Asthma. 2014;51(7):756–61.

    Article  CAS  Google Scholar 

  51. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;352(21):2163–73.

    Article  CAS  PubMed  Google Scholar 

  52. Petsky HL, Cates CJ, Li A, Kynaston JA, Turner C, Chang AB. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2009;4:CD006340.

    Google Scholar 

  53. Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol. 2009;21(12):1303–9.

    Article  CAS  PubMed  Google Scholar 

  54. 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 Lond Engl. 2012;380(9842):651–9. In this double-blind, placebo-controlled trial, mepolizumab, a monoclonal antibody against interleukin 5, is associated with a reduced frequency of exacerbations in patients with a history of recurrent severe asthma exacerbations, and signs of eosinophilic inflammation (blood eosinophilia, sputum eosinophilia or high FeNO).

    Article  CAS  Google Scholar 

  55. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–207. In this double-blind, placebo-controlled trial, mepolizumab was shown to be effective at reducing frequency of exacerbations and improve systemic corticosteroid tapering in patients with exacerbation-prone asthma, and a blood eosinophil count of ≥150 cell per microliter.

    Article  PubMed  Google Scholar 

  56. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97.

    Article  PubMed  Google Scholar 

  57. Acland JD, Gould AH. Normal variation in the count of circulating eosinophils in man. J Physiol. 1956;133(2):456–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Desai D, Newby C, Symon FA, Haldar P, Shah S, Gupta S, et al. Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med. 2013;188(6):657–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010;107(32):14170–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Johansson MW, Evans MD, Crisafi GM, Holweg CTJ, Matthews JG, Jarjour NN. Serum periostin is associated with type 2 immunity in severe asthma. J Allergy Clin Immunol. 2016;137(6):1904–7.e2.

  61. Zhu S, Barbe MF, Liu C, Hadjiargyrou M, Popoff SN, Rani S, et al. Periostin-like-factor in osteogenesis. J Cell Physiol. 2009;218(3):584–92.

    Article  CAS  PubMed  Google Scholar 

  62. Shiobara T, Chibana K, Watanabe T, Arai R, Horigane Y, Nakamura Y, et al. 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. 2016;17:28.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Brightling CE, Chanez P, Leigh R, O’Byrne PM, Korn S, She D, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692–701.

    Article  CAS  PubMed  Google Scholar 

  64. Baines KJ, Simpson JL, Wood LG, Scott RJ, Fibbens NL, Powell H, et al. Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. J Allergy Clin Immunol. 2014;133(4):997–1007.

    Article  CAS  PubMed  Google Scholar 

  65. 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):153–60. 160.e1–9.

    Article  CAS  PubMed  Google Scholar 

  66. Yan X, Chu J-H, Gomez J, Koenigs M, Holm C, He X, et al. Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma. Am J Respir Crit Care Med. 2015;191(10):1116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kupczyk M, Dahlen B, Sterk PJ, Nizankowska-Mogilnicka E, Papi A, Bel EH, et al. Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma. Allergy. 2014;69(9):1198–204.

    Article  CAS  PubMed  Google Scholar 

  68. Boudier A, Curjuric I, Basagaña 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.

    Article  PubMed  Google Scholar 

  69. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med. 2007;175(7):661–6.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Akerman MJH, Calacanis CM, Madsen MK. Relationship between asthma severity and obesity. J Asthma Off J Assoc Care Asthma. 2004;41(5):521–6.

    Article  Google Scholar 

  71. Holguin F, Comhair SAA, Hazen SL, Powers RW, Khatri SS, Bleecker ER, et al. An association between l-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype. Am J Respir Crit Care Med. 2013;187(2):153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med [Internet]. 2016 Jun [cited 2016 Jun 8]; Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260016300480. Cross-sectional study showing that systemic IL-6 inflammation and clinical features of metabolic dysfunction, occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, and are associated with more severe asthma. This study provides a strong rationale for clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma and high plasma IL-6.

  73. Halter JB, Musi N, Horne FM, Crandall JP, Goldberg A, Harkless L, et al. Diabetes and cardiovascular disease in older adults: current status and future directions. Diabetes. 2014;63(8):2578–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110(8):1097–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update a report from the American Heart Association. Circulation. 2015;131(4):e29–322.

    Article  PubMed  Google Scholar 

  76. Zein JG, Dweik RA, Comhair SA, Bleecker ER, Moore WC, Peters SP, et al. Asthma is more severe in older adults. PLoS One. 2015;10(7):e0133490.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Stoy PJ, Roitman-Johnson B, Walsh G, Gleich GJ, Mendell N, Yunis E, et al. Aging and serum immunoglobulin E levels, immediate skin tests, RAST. J Allergy Clin Immunol. 1981;68(6):421–6.

    Article  CAS  PubMed  Google Scholar 

  78. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372(9643):1049–57.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael C. Peters.

Ethics declarations

Conflict of Interest

Drs. Peters, Nguyen, and Dunican declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

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

Additional information

This article is part of the Topical Collection on Asthma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peters, M.C., Nguyen, ML.T. & Dunican, E.M. Biomarkers of Airway Type-2 Inflammation and Integrating Complex Phenotypes to Endotypes in Asthma. Curr Allergy Asthma Rep 16, 71 (2016). https://doi.org/10.1007/s11882-016-0651-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-016-0651-4

Keywords

Navigation