Advertisement

Predictive Biomarkers for Asthma Therapy

  • Sarah K. Medrek
  • Amit D. Parulekar
  • Nicola A. HananiaEmail author
Asthma (WJ Calhoun and V Ortega, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Asthma

Abstract

Purpose of Review

Asthma is a heterogeneous disease characterized by multiple phenotypes. Treatment of patients with severe disease can be challenging. Predictive biomarkers are measurable characteristics that reflect the underlying pathophysiology of asthma and can identify patients that are likely to respond to a given therapy. This review discusses current knowledge regarding predictive biomarkers in asthma.

Recent Findings

Recent trials evaluating biologic therapies targeting IgE, IL-5, IL-13, and IL-4 have utilized predictive biomarkers to identify patients who might benefit from treatment. Other work has suggested that using composite biomarkers may offer enhanced predictive capabilities in tailoring asthma therapy.

Summary

Multiple biomarkers including sputum eosinophil count, blood eosinophil count, fractional concentration of nitric oxide in exhaled breath (FeNO), and serum periostin have been used to identify which patients will respond to targeted asthma medications. Further work is needed to integrate predictive biomarkers into clinical practice.

Keywords

Asthma Therapy Biomarkers Phenotypes Endotypes Biologics 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Hanania has received honoraria from serving on advisory boards or as a consultant with Novartis, Boehringer Ingelheim, GlaxoSmithKline, Astra Zeneca, and Roche. His institution has received grant support for research from GSK, Boehringer Ingelheim, Cheisi, Astra Zeneca, and Roche. Dr. Parulekar reports personal fees from AstraZeneca. Dr. Medrek declares 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.

References

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

  1. 1.
    • GINA. Global strategy for asthma management and prevention. Global Initiative for Asthma. 2017. The updated asthma guidelines from GINA. Google Scholar
  2. 2.
    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.  https://doi.org/10.1186/1471-2458-12-204.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson CA, et al. National surveillance of asthma: United States. Vital Health Stat 3. 2001-2010;2012(35):1–58.Google Scholar
  4. 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.  https://doi.org/10.1183/09031936.00202013. Treatment guidelines from the ATS for patients with severe asthma. PubMedCrossRefGoogle Scholar
  5. 5.
    Heaney LG, Djukanovic R, Woodcock A, Walker S, Matthews JG, Pavord ID, et al. Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax. 2016;71(2):187–9.  https://doi.org/10.1136/thoraxjnl-2015-207326.PubMedCrossRefGoogle Scholar
  6. 6.
    Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368(9537):804–13.  https://doi.org/10.1016/S0140-6736(06)69290-8.PubMedCrossRefGoogle Scholar
  7. 7.
    Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107–19.  https://doi.org/10.1016/S0140-6736(08)61452-X.PubMedCrossRefGoogle Scholar
  8. 8.
    Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.  https://doi.org/10.1067/mcp.2001.113989.CrossRefGoogle Scholar
  9. 9.
    Robb MA, McInnes PM, Califf RM. Biomarkers and surrogate endpoints: developing common terminology and definitions. JAMA. 2016;315(11):1107–8.  https://doi.org/10.1001/jama.2016.2240.PubMedCrossRefGoogle Scholar
  10. 10.
    FDA-NIH biomarker working group BEST (biomarkers, endpoints, and other tools) resource Silver Spring (MD): Food and Drug Administration (US). 2016.Google Scholar
  11. 11.
    Fricker M, Heaney LG, Upham JW. Can biomarkers help us hit targets in difficult-to-treat asthma? Respirology. 2017;  https://doi.org/10.1111/resp.13014.
  12. 12.
    Parulekar AD, Diamant Z, Hanania NA. Role of T2 inflammation biomarkers in severe asthma. Curr Opin Pulm Med. 2016;22(1):59–68.  https://doi.org/10.1097/MCP.0000000000000231.PubMedCrossRefGoogle Scholar
  13. 13.
    Vijverberg SJ, Hilvering B, Raaijmakers JA, Lammers JW, Maitland-van der Zee AH, Koenderman L. Clinical utility of asthma biomarkers: from bench to bedside. Biologics. 2013;7:199–210.  https://doi.org/10.2147/BTT.S29976.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Rackemann FM. A working classification of asthma. Am J Med. 1947;3(5):601–6.PubMedCrossRefGoogle Scholar
  15. 15.
    • Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999;160(3):1001–8.  https://doi.org/10.1164/ajrccm.160.3.9812110. Key study which helped to establish the eosinophilic asthma endotype PubMedCrossRefGoogle Scholar
  16. 16.
    Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56.  https://doi.org/10.1038/ni.3049.PubMedCrossRefGoogle Scholar
  17. 17.
    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.  https://doi.org/10.1164/rccm.200903-0392OC.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11(1):54–61.  https://doi.org/10.1111/j.1440-1843.2006.00784.x.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Brown HM. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet. 1958;2(7059):1245–7.PubMedCrossRefGoogle Scholar
  21. 21.
    • Petsky HL, Kynaston JA, Turner C, Li AM, Cates CJ, Lasserson TJ, et al. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev. 2007;2:CD005603.  https://doi.org/10.1002/14651858.CD005603.pub2. Meta-analysis which validated the use of sputum eosinophils to guide corticosteroid therapy Google Scholar
  22. 22.
    Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21.  https://doi.org/10.1016/S0140-6736(02)11679-5.PubMedCrossRefGoogle Scholar
  23. 23.
    Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483–94.  https://doi.org/10.1183/09031936.06.00137704.PubMedCrossRefGoogle Scholar
  24. 24.
    Chlumsky J, Striz I, Terl M, Vondracek J. Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. J Int Med Res. 2006;34(2):129–39.  https://doi.org/10.1177/147323000603400202.PubMedCrossRefGoogle Scholar
  25. 25.
    Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71.  https://doi.org/10.1164/rccm.200701-085OC.PubMedCrossRefGoogle Scholar
  26. 26.
    Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84.  https://doi.org/10.1056/NEJMoa0808991.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93.  https://doi.org/10.1056/NEJMoa0805435.PubMedCrossRefGoogle Scholar
  28. 28.
    Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9.  https://doi.org/10.1016/S0140-6736(12)60988-X.PubMedCrossRefGoogle Scholar
  29. 29.
    Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184(10):1125–32.  https://doi.org/10.1164/rccm.201103-0396OC.PubMedCrossRefGoogle Scholar
  30. 30.
    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.  https://doi.org/10.1056/NEJMoa1304048.PubMedCrossRefGoogle Scholar
  31. 31.
    Gonem S, Berair R, Singapuri A, Hartley R, Laurencin MF, Bacher G, 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 Respir Med. 2016;4(9):699–707.  https://doi.org/10.1016/S2213-2600(16)30179-5.PubMedCrossRefGoogle Scholar
  32. 32.
    • Westerhof GA, Korevaar DA, Amelink M, de Nijs SB, de Groot JC, Wang J, et al. Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes. Eur Respir J. 2015;46(3):688–96.  https://doi.org/10.1183/09031936.00012415. Analysis which evaluated if sputum eosinophilia was predicted by other, easier-to-measure, biomarkers PubMedCrossRefGoogle Scholar
  33. 33.
    Wagener AH, de Nijs SB, Lutter R, Sousa AR, Weersink EJ, Bel EH, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70(2):115–20.  https://doi.org/10.1136/thoraxjnl-2014-205634.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang XY, Simpson JL, Powell H, Yang IA, Upham JW, Reynolds PN, et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy. 2014;44(9):1137–45.  https://doi.org/10.1111/cea.12345.PubMedCrossRefGoogle Scholar
  35. 35.
    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.  https://doi.org/10.1016/S2213-2600(15)00050-8.PubMedCrossRefGoogle Scholar
  36. 36.
    Horn BR, Robin ED, Theodore J, Van Kessel A. Total eosinophil counts in the management of bronchial asthma. N Engl J Med. 1975;292(22):1152–5.  https://doi.org/10.1056/NEJM197505292922204.PubMedCrossRefGoogle Scholar
  37. 37.
    Taylor KJ, Luksza AR. Peripheral blood eosinophil counts and bronchial responsiveness. Thorax. 1987;42(6):452–6.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132(4):821–7e1-5.  https://doi.org/10.1016/j.jaci.2013.06.007.PubMedCrossRefGoogle Scholar
  39. 39.
    Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med. 2015;3(11):849–58.  https://doi.org/10.1016/S2213-2600(15)00367-7.PubMedCrossRefGoogle Scholar
  40. 40.
    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.  https://doi.org/10.1056/NEJMoa1403291.PubMedCrossRefGoogle Scholar
  41. 41.
    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.  https://doi.org/10.1056/NEJMoa1403290.PubMedCrossRefGoogle Scholar
  42. 42.
    Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, 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 Respir Med. 2015;3(5):355–66.  https://doi.org/10.1016/S2213-2600(15)00042-9.PubMedCrossRefGoogle Scholar
  43. 43.
    Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016;150(4):789–98.  https://doi.org/10.1016/j.chest.2016.03.032.PubMedCrossRefGoogle Scholar
  44. 44.
    Corren J, Weinstein S, Janka L, Zangrilli J, Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.  https://doi.org/10.1016/j.chest.2016.03.018.PubMedCrossRefGoogle Scholar
  45. 45.
    Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2(11):879–90.  https://doi.org/10.1016/S2213-2600(14)70201-2.PubMedCrossRefGoogle Scholar
  46. 46.
    Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–27.  https://doi.org/10.1016/S0140-6736(16)31324-1.PubMedCrossRefGoogle Scholar
  47. 47.
    FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha 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;388(10056):2128–41.  https://doi.org/10.1016/S0140-6736(16)31322-8.PubMedCrossRefGoogle Scholar
  48. 48.
    Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;  https://doi.org/10.1056/NEJMoa1703501.
  49. 49.
    Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804–11.  https://doi.org/10.1164/rccm.201208-1414OC.PubMedCrossRefGoogle Scholar
  50. 50.
    Busse W, Spector S, Rosen K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol. 2013;132(2):485–486 e11.  https://doi.org/10.1016/j.jaci.2013.02.032.PubMedCrossRefGoogle Scholar
  51. 51.
    Tajiri T, Matsumoto H, Gon Y, Ito R, Hashimoto S, Izuhara K, et al. Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma. Allergy. 2016;71(10):1472–9.  https://doi.org/10.1111/all.12922.PubMedCrossRefGoogle Scholar
  52. 52.
    Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602–15.  https://doi.org/10.1164/rccm.9120-11ST.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Lane C, Knight D, Burgess S, Franklin P, Horak F, Legg J, et al. Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath. Thorax. 2004;59(9):757–60.  https://doi.org/10.1136/thx.2003.014894.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Dupont LJ, Rochette F, Demedts MG, Verleden GM. Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):894–8.  https://doi.org/10.1164/ajrccm.157.3.9709064.PubMedCrossRefGoogle Scholar
  56. 56.
    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.  https://doi.org/10.1056/NEJMoa043596.PubMedCrossRefGoogle Scholar
  57. 57.
    Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev. 2016;9:CD011440.  https://doi.org/10.1002/14651858.CD011440.pub2.PubMedGoogle Scholar
  58. 58.
    Essat M, Harnan S, Gomersall T, Tappenden P, Wong R, Pavord I, et al. Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review. Eur Respir J. 2016;47(3):751–68.  https://doi.org/10.1183/13993003.01882-2015.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hanania NA, Noonan M, Corren J, Korenblat P, Zheng Y, Fischer SK, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748–56.  https://doi.org/10.1136/thoraxjnl-2014-206719.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med. 2012;186(11):1102–8.  https://doi.org/10.1164/rccm.201204-0587OC.PubMedCrossRefGoogle Scholar
  61. 61.
    Buchvald F, Baraldi E, Carraro S, Gaston B, De Jongste J, Pijnenburg MW, et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol. 2005;115(6):1130–6.  https://doi.org/10.1016/j.jaci.2005.03.020.PubMedCrossRefGoogle Scholar
  62. 62.
    Borrill Z, Clough D, Truman N, Morris J, Langley S, Singh D. A comparison of exhaled nitric oxide measurements performed using three different analysers. Respir Med. 2006;100(8):1392–6.  https://doi.org/10.1016/j.rmed.2005.11.018.PubMedCrossRefGoogle Scholar
  63. 63.
    Wu LC, Zarrin AA. The production and regulation of IgE by the immune system. Nat Rev Immunol. 2014;14(4):247–59.  https://doi.org/10.1038/nri3632.PubMedCrossRefGoogle Scholar
  64. 64.
    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.  https://doi.org/10.1056/NEJM198902023200502.PubMedCrossRefGoogle Scholar
  65. 65.
    Sherrill DL, Lebowitz MD, Halonen M, Barbee RA, Burrows B. Longitudinal evaluation of the association between pulmonary function and total serum IgE. Am J Respir Crit Care Med. 1995;152(1):98–102.  https://doi.org/10.1164/ajrccm.152.1.7599870.PubMedCrossRefGoogle Scholar
  66. 66.
    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.  https://doi.org/10.1067/mai.2001.117880.PubMedCrossRefGoogle Scholar
  67. 67.
    Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD003559.  https://doi.org/10.1002/14651858.CD003559.pub4.Google Scholar
  68. 68.
    Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005;60(3):302–8.  https://doi.org/10.1111/j.1398-9995.2004.00770.x.PubMedCrossRefGoogle Scholar
  69. 69.
    Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006;118(1):98–104.  https://doi.org/10.1016/j.jaci.2006.02.046.PubMedCrossRefGoogle Scholar
  70. 70.
    Yuyama N, Davies DE, Akaiwa M, Matsui K, Hamasaki Y, Suminami Y, et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine. 2002;19(6):287–96.PubMedCrossRefGoogle Scholar
  71. 71.
    Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130(3):647–654 e10.  https://doi.org/10.1016/j.jaci.2012.06.025.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132(2):305–312 e3.  https://doi.org/10.1016/j.jaci.2013.04.050.PubMedCrossRefGoogle Scholar
  73. 73.
    James A, Janson C, Malinovschi A, Holweg C, Alving K, Ono J, et al. Serum periostin relates to type-2 inflammation and lung function in asthma; data from the large population-based cohort Swedish GA(2)LEN. Allergy. 2017;  https://doi.org/10.1111/all.13181.
  74. 74.
    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.  https://doi.org/10.1056/NEJMoa1106469.PubMedCrossRefGoogle Scholar
  75. 75.
    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.  https://doi.org/10.1016/S2213-2600(15)00197-6.PubMedCrossRefGoogle Scholar
  76. 76.
    Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P, Paggiaro P, 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.  https://doi.org/10.1016/S2213-2600(16)30265-X.PubMedCrossRefGoogle Scholar
  77. 77.
    Semprini R, Caswell-Smith R, Fingleton J, Holweg C, Matthews J, Weatherall M, et al. Longitudinal variation of serum periostin levels in adults with stable asthma. J Allergy Clin Immunol. 2017;139(5):1687–1688 e9.  https://doi.org/10.1016/j.jaci.2016.11.041.PubMedCrossRefGoogle Scholar
  78. 78.
    Izuhara K, Conway SJ, Moore BB, Matsumoto H, Holweg CT, Matthews JG, et al. Roles of periostin in respiratory disorders. Am J Respir Crit Care Med. 2016;193(9):949–56.  https://doi.org/10.1164/rccm.201510-2032PP.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Nieto-Fontarigo JJ, Gonzalez-Barcala FJ, San Jose E, Arias P, Nogueira M, Salgado FJ. CD26 and asthma: a comprehensive review. Clin Rev Allergy Immunol. 2016;  https://doi.org/10.1007/s12016-016-8578-z.
  80. 80.
    Saha SK, Berry MA, Parker D, Siddiqui S, Morgan A, May R, et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol. 2008;121(3):685–91.  https://doi.org/10.1016/j.jaci.2008.01.005.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–8.  https://doi.org/10.1183/09031936.00223411.PubMedCrossRefGoogle Scholar
  82. 82.
    Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR Jr. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003;111(1 Suppl):S18–34. discussion S-6PubMedCrossRefGoogle Scholar
  83. 83.
    Pavord ID, Ward R, Woltmann G, Wardlaw AJ, Sheller JR, Dworski R. Induced sputum eicosanoid concentrations in asthma. Am J Respir Crit Care Med. 1999;160(6):1905–9.  https://doi.org/10.1164/ajrccm.160.6.9903114.PubMedCrossRefGoogle Scholar
  84. 84.
    Aggarwal S, Moodley YP, Thompson PJ, Misso NL. Prostaglandin E2 and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation. Clin Exp Allergy. 2010;40(1):85–93.  https://doi.org/10.1111/j.1365-2222.2009.03386.x.PubMedGoogle Scholar
  85. 85.
    Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol. 2005;115(2):233–42.  https://doi.org/10.1016/j.jaci.2004.11.014.PubMedCrossRefGoogle Scholar
  86. 86.
    Cai C, Yang J, Hu S, Zhou M, Guo W. Relationship between urinary cysteinyl leukotriene E4 levels and clinical response to antileukotriene treatment in patients with asthma. Lung. 2007;185(2):105–12.  https://doi.org/10.1007/s00408-006-0001-8.PubMedCrossRefGoogle Scholar
  87. 87.
    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.  https://doi.org/10.1164/rccm.201109-1640OC.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    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.  https://doi.org/10.1164/rccm.200906-0896OC.PubMedCrossRefGoogle Scholar
  89. 89.
    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.  https://doi.org/10.1164/rccm.200711-1754OC.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    • Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557–63.e5.  https://doi.org/10.1016/j.jaci.2013.10.011. Cluster analysis of patients with severe asthma that found four phenotypic clusters based on airway inflammation patterns; increased sputum neutrophils were associated with a more severe presentation PubMedCrossRefGoogle Scholar
  91. 91.
    Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148–55.  https://doi.org/10.1164/rccm.200707-1134OC.PubMedCrossRefGoogle Scholar
  92. 92.
    Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322–9.  https://doi.org/10.1136/thoraxjnl-2012-202698.PubMedCrossRefGoogle Scholar
  93. 93.
    Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, 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;  https://doi.org/10.1016/S0140-6736(17)31281-3.
  94. 94.
    O'Byrne PM, Metev H, Puu M, Richter K, Keen C, Uddin M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(10):797–806.  https://doi.org/10.1016/S2213-2600(16)30227-2.PubMedCrossRefGoogle Scholar
  95. 95.
    Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, et al. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 2009;123(5):1185–7.  https://doi.org/10.1016/j.jaci.2009.02.024.PubMedCrossRefGoogle Scholar
  96. 96.
    Chesne J, Braza F, Mahay G, Brouard S, Aronica M, Magnan A. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med. 2014;190(10):1094–101.  https://doi.org/10.1164/rccm.201405-0859PP.PubMedCrossRefGoogle Scholar
  97. 97.
    Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294–302.  https://doi.org/10.1164/rccm.201212-2318OC.PubMedCrossRefGoogle Scholar
  98. 98.
    Aldakheel FM, Thomas PS, Bourke JE, Matheson MC, Dharmage SC, Lowe AJ. Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: a systematic review. Allergy. 2016;71(6):741–57.  https://doi.org/10.1111/all.12865.PubMedCrossRefGoogle Scholar
  99. 99.
    Horvath I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26(3):523–48.  https://doi.org/10.1183/09031936.05.00029705.PubMedCrossRefGoogle Scholar
  100. 100.
    Antczak A, Kurmanowska Z, Kasielski M, Nowak D. Inhaled glucocorticosteroids decrease hydrogen peroxide level in expired air condensate in asthmatic patients. Respir Med. 2000;94(5):416–21.  https://doi.org/10.1053/rmed.1999.0801.PubMedCrossRefGoogle Scholar
  101. 101.
    Jackson AS, Sandrini A, Campbell C, Chow S, Thomas PS, Yates DH. Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. Am J Respir Crit Care Med. 2007;175(3):222–7.  https://doi.org/10.1164/rccm.200601-107OC.PubMedCrossRefGoogle Scholar
  102. 102.
    Rufo JC, Madureira J, Fernandes EO, Moreira A. Volatile organic compounds in asthma diagnosis: a systematic review and meta-analysis. Allergy. 2016;71(2):175–88.  https://doi.org/10.1111/all.12793.PubMedCrossRefGoogle Scholar
  103. 103.
    Robroeks CM, van Berkel JJ, Jobsis Q, van Schooten FJ, Dallinga JW, Wouters EF, et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. Eur Respir J. 2013;42(1):98–106.  https://doi.org/10.1183/09031936.00010712.PubMedCrossRefGoogle Scholar
  104. 104.
    van der Schee MP, Palmay R, Cowan JO, Taylor DR. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy. 2013;43(11):1217–25.  https://doi.org/10.1111/cea.12147.PubMedCrossRefGoogle Scholar
  105. 105.
    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.  https://doi.org/10.1016/j.jaci.2013.12.1091.PubMedCrossRefGoogle Scholar
  106. 106.
    Heffler E, Allegra A, Pioggia G, Picardi G, Musolino C, Gangemi S. MicroRnas profiling in asthma: potential biomarkers and therapeutic targets. Am J Respir Cell Mol Biol. 2017;  https://doi.org/10.1165/rcmb.2016-0231TR.
  107. 107.
    Durack J, Lynch SV, Nariya S, Bhakta NR, Beigelman A, Castro M, et al. Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment. J Allergy Clin Immunol. 2016;  https://doi.org/10.1016/j.jaci.2016.08.055.
  108. 108.
    • Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, et al. Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. J Allergy Clin Immunol. 2017;  https://doi.org/10.1016/j.jaci.2016.11.038. Recent analysis which suggests that using a composite of biomarkers can more accurately predict a patient’s endotype.
  109. 109.
    Nagasaki T, Matsumoto H, Kanemitsu Y, Izuhara K, Tohda Y, Horiguchi T, et al. Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma. Am J Respir Crit Care Med. 2014;190(12):1449–52.  https://doi.org/10.1164/rccm.201407-1290LE.PubMedCrossRefGoogle Scholar
  110. 110.
    Montuschi P, Santonico M, Mondino C, Pennazza G, Mantini G, Martinelli E, et al. Diagnostic performance of an electronic nose, fractional exhaled nitric oxide, and lung function testing in asthma. Chest. 2010;137(4):790–6.  https://doi.org/10.1378/chest.09-1836.PubMedCrossRefGoogle Scholar
  111. 111.
    Levy BD, Noel PJ, Freemer MM, Cloutier MM, Georas SN, Jarjour NN, et al. Future research directions in asthma. An NHLBI working group report. Am J Respir Crit Care Med. 2015;192(11):1366–72.  https://doi.org/10.1164/rccm.201505-0963WS.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192(6):660–8.  https://doi.org/10.1164/rccm.201504-0763PP.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Sarah K. Medrek
    • 1
  • Amit D. Parulekar
    • 2
  • Nicola A. Hanania
    • 1
    Email author
  1. 1.Section of Pulmonary, Critical Care and Sleep MedicineBaylor College of MedicineHoustonUSA
  2. 2.Section of Pulmonary, Critical Care and Sleep MedicineBaylor College of MedicineHoustonUSA

Personalised recommendations