698
Views
27
CrossRef citations to date
0
Altmetric
Review

Molecular phenotyping and biomarker development: are we on our way towards targeted therapy for severe asthma?

, , , , &

References

  • Papers of special note have been highlighted as:
  • * of interest
  • ** of considerable interest
  • Global Initiative for Asthma (GINA). From the Global Strategy for Asthma Management and Prevention [Internet]. 2015 [cited 2015 Jul 10]. Available from: http://www.ginasthma.org/
  • Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–373.
  • Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126:926–938.
  • Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363:301–304. Erratum in: N Engl J Med. 2010;363:1092.
  • Cox C, Kjarsgaard M, Surette MG, et al. A multidimensional approach to the management of severe asthma: inflammometry, molecular microbiology and bronchial thermoplasty. Can Respir J. 2015;22:221–224. pii: 16891.
  • Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012;42:650–658.
  • Gustafsson M, Nestor CE, Zhang H, et al. Modules, networks and systems medicine for understanding disease and aiding diagnosis. Genome Med. 2014;6:82.
  • Drazen JM. A step toward personalized asthma treatment. N Engl J Med. 2011;365:1245–1246.
  • Braido F, Holgate S, Canonica GW. From “blockbusters” to “biosimilars”: an opportunity for patients, medical specialists and health care providers. Pulm Pharmacol Ther. 2012;25:483–486.
  • Cazzola M, Novelli G. Biomarkers in COPD. Pulm Pharmacol Ther. 2010;23:493–500.
  • Rossi R, De Palma A, Benazzi L, et al. Biomarker discovery in asthma and COPD by proteomic approaches. Proteomics Clin Appl. 2014;8:901–915.
  • Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130:647–654.
  • Wagener AH, De Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70:115–120.
  • Peters MC, Mekonnen ZK, Yuan S, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133:388–394.
  • Oreo KM, Gibson PG, Simpson JL, et al. Sputum ADAM-8 expression in increased in severe asthma and COPD. Clin Experim Allergy. 2013;44:342–352.
  • Coleman JM, Naik C, Holguin F, et al. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset. Thorax. 2012;67:1061–1066.
  • Hosoki K, Ying S, Corrigan C, et al. Analysis of a panel of 48 cytokines in BAL fluids specifically identifies IL-8 levels as the only cytokine that distinguishes controlled asthma from uncontrolled asthma, and correlates inversely with FEV1. PLoS One. 2015;10:e0126035.
  • Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388–395.

**Discovery of phenotypes on the degree of Th2 inflammation.

  • Riccio AM, Dal Negro RW, Micheletto C, et al. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol. 2012;25:475–484.
  • Mauri P, Riccio AM, Rossi R, et al. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett. 2014;162(1 Pt A):2–10.
  • Gemicioglu B, Musellim B, Dogan I, et al. Fractional exhaled nitric oxide (FeNo) in different asthma phenotypes. Allergy Rhinol. 2014;5:157–161.
  • Hanania NA, Wenzel S, Rosen K, 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;187:804–811.

**An interesting and complete overview on known and potential biomarkers of omalizumab effects in severe asthma management.

  • Peirsman EJ, Carvelli TJ, Hage PY, et al. Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial. Pediatr Pulmonol. 2014;49:624–631.
  • Yang S, Park J, Lee YK, et al. Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children. Respir Med. 2015;109:572–579.
  • Di Gangi IM, Pirillo P, Carraro S, et al. Online trapping and enrichment ultra-performance liquid chromatography-tandem mass spectrometry method for sensitive measurement of “arginine-asymmetric dimethylarginine cycle” biomarkers in human exhaled breath condensate. Anal Chim Acta. 2012;754:67–74.
  • Carraro S, Giordano G, Reniero F, et al. Asthma severity in childhood and metabolomic profiling of breath condensate. Allergy. 2013;68:110–117.
  • Kazani S, Planaguma A, Ono E, et al. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol. 2013;132:547–553.
  • Schwarz K, Biller H, Windt H, et al. Characterization of exhaled particles from the human lungs in airway obstruction. J Aerosol Med Pulm Drug Deliv. 2015;28:52–58.
  • Katz LE, Gleich GJ, Hartley BF, et al. Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma. Ann Am Thorac Soc. 2014;11:531–536.
  • Cai C, Yang J, Hu S, et al. Relationship between urinary cysteinyl leukotriene E4 levels and clinical response to antileukotriene treatment in patients with asthma. Lung. 2007;185:105–112.
  • Mattarucchi E, Baraldi E, Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites. Biomed Chromatogr. 2012;26:89–94.
  • Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129:974-82.e13.
  • Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133:1557-63.e5.
  • Simpson JL, McElduff P, Gibson PG. Assessment and reproducibility of non-eosinophilic asthma using induced sputum. Respiration. 2010;79:147–151.
  • Rossall MR, Cadden PA, Molphy SD, et al. Repeatability of induced sputum measurements in moderate to severe asthma. Respir Med. 2014;108:1566–1568.
  • Mosmann TR, Cherwinski HM, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of limphokine activities and secreted proteins. J Immunol. 1986;136:2348–2357.
  • Del Prete GF, De Carli M, Mastromauro C, et al., J Clin Invest. 1991;88:346–350.
  • Dunn RM, Wechsler ME. Anti-interleukin therapy in asthma. Clin Pharmacol Ther. 2015;97:55–65.
  • Mory Y, Iwasaki H, Kohno K, et al. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitors. J Exp Med. 2009;206:183–193.
  • Farahani R, Sherkat R, Hakemi MG, et al. Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33) and asthma. Adv Biomed Res. 2014;3:127.
  • Siracusa MC, Comeau MR, Artis D. New insights into basophils biology: initiatiors, regulators, and effectors of type 2 inflammation. Ann N Y Acad Sci. 2011;1217:166–177.
  • Vatrella A, Fabozzi I, Calabrese C, et al. Dupilumab: a novel treatment for asthma. J Asthma Allergy. 2014;7:123–130.
  • Dweik RA, Boggs PB, Erzurum SC, 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;184:602–615.
  • Conway SJ, Izuhara K, Kudo Y, et al. The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci. 2014;71:1279–1288.
  • Sidhu SS, Yuan S, Innes AL, et al. Roles of epithelial cell-derived periostin in TFG-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci USA. 2010;107:14170–14175.
  • Matsumoto H. Serum periostin: a novel biomarker for asthma management. Allergol Int. 2014;63:153–160.
  • Wu D, Zhou J, Bi H, et al. CCL11 as a potential diagnostic marker for asthma?. J Asthma. 2014;51:847–854.
  • Comhair SA, Erzurum SC. Redox control of asthma: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2010;12:93–124.
  • Raundhal M, Morse C, Khare A, et al. High IFN-gamma and slow SLPI mark severe asthma in mice and humans. J Clin Invest. 2015;125:3037–3050.
  • Roussel L, Houle F, Chan C, et al IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J Immunol. 2010;184:4531–4537.
  • Phenotype. Merriam-Webster’s Collegiate® English Dictionary [Internet]. 12th ed. Merriam Webster Inc.; 2008 [cited 2015 Jul 16]. Available from: http://merriam-webster.com
  • Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. The. Journal of Allergy and Clinical Immunology. 2011;127:355–360.
  • Chung KF. Defining phenotypes in asthma: a step towards personalized medecine. Drugs. 2014;74:719–728.
  • Wenzel SE, Schwartz LB, Langmack EL, 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;160:1001–1008.

**Authors identified for the first time neutrophilic inflammation in mild asthmatics and found an association between clinical variables and different amounts of eosinophilic inflammation.

  • Gibson PG, Simpson JL, Hankin R, et al. Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax. 2003;58:116–121.
  • Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113:101–108.

**An intresting study on phenotypic differences between early-onset severe asthma as compared with late-onset disease.

  • Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181:315–323. 37.
  • Fitzpatrick AM, Teague WG, Meyers DA, 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. 2011;127:382–389.
  • Schatz M, Hsu JW, Zeiger RS, et al. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma. J Allergy Clin Immunol. 2014;133:1549–1556.
  • Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci U S A. 2007;104:15858–15863.

**This study began the concept of molecular phenotyping.

**High serum periostin identified as predicting biomarkers of lebrikizumab treatment outcome.

  • Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Resp J. 2013;41:330–338.
  • Humbert M, Berger W, Rapatz G, et al. Add-on omalizumab improves day-to-day symptoms in inadequately controlled severe persistent allergic asthma. Allergy. 2008;63:592–596.
  • Hanania NA, Alpan O, Hamilos DL, et al Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154:573–582.
  • Corren J, Busse W, Meltzer EO, et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralfa antagonist, in patients with asthma. Am J Respir Crit Care Med. 2010;181:788–796.
  • Slager RE, Hawkins GA, Ampleford EJ, 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. 2010;126:875–878.
  • Slager RE, Otulana BA, Hawkins GA, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J Allergy Clin Immunol. 2012;130:516-22. e4.
  • Chu HW, Balzar S, Wesrcott JY, et al. Expression and activation of 15-lipoxygenase pathway in severe asthma: relationship to eosinophilic phenotype and collagen deposition. Clin Exp Alllergy. 2002;32:1558–1565.
  • Woolley KL, Gibson PG, Carty K, et al. Eosinophil apoptosis and the resolution of airway inflammation in asthma. Am J Respir Crit Care Med. 1996;154:237–243.
  • Ten Brinke A, Zwinderman AH, Sterk PJ, et al. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med. 2004;170:601–605.
  • Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651–659.
  • Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–984.
  • Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med. 2014;371:1249–1251.
  • Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Resp Crit Care Med. 2011;184:1125–1132.
  • Dahlèn SE, Malmström K, Nizankowska 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. 2002;165:9–14.
  • Wenzel S, Wilbraham D, Fuller R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370:1422–1431.
  • Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophils levels. N Engl J Med. 2013;368:2455–2466.

*Effectiveness of anti-IL4Ralpha on Th2 inflammation and pulmonary function.

  • Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11:577–584.
  • Black JL, Roth M. Intrinsic asthma: is it intrinsic to the smooth muscle?. Clin Exp Allergy. 2009;39:962–965.
  • Holguin F, Bleecker ER, Busse WW, et al. Obesity and asthma: an association modified by age of asthma onset. J Allergy Clin Immunol. 2011;127:1486-93. e2.
  • Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma phenotype?. J Appl Physiol. 2010;108:729–734.
  • Calixto MC, Lintomen L, Schenka A, et al. Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. Br J Pharmacol. 2010;159:617–625.
  • Holguin F, Rojas M, Brown LA, et al. Airway and plasma leptin and adiponectin in lean and obese asthmatics and controls. J Asthma. 2011;48:217–223.
  • Aydin M, Koca C, Ozol D, et al. Interaction of metabolic syndrome with asthma in post-menopausal women: role of adipokines. Inflammation. 2013;36:1232–1238.
  • Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. 2011;128:508-515. e2.
  • Lombardi C, Gargioni S, Gardinazzi A, et al. Impact of bariatric surgery on pulmonary function and nitric oxide in asthmatic and non-asthmatic obese patients. J Asthma. 2011;48:553–557.
  • Kato T, Takeda Y, Nakata T, et al Inhibition by dexamethasone of human neutrophil apoptosis in vitro. Nat Immun. 1995;14:198–208.
  • Baines KJ, Simpson JL, Wood LG, et al. Transcriptional phenotypes of asthma defined by gene expression profiling in induced sputum sample. J Allergy Clin Immunol. 2011;127:153–160.
  • Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179:549–558.
  • Baines KJ, Simpson JL, Wood LG, et al. Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma. Thorax. 2011;66:942–947.
  • Doe C, Bafadhel M, Siddiqui S, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest. 2010;138:1140–1147.
  • Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177:148–155.
  • Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42:1097–1103.
  • Balzar S, Fajt ML, Comhair SA, et al. Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. Am J Respir Crit Care Med. 2011;183:299–309.
  • Bujarski S, Parulekar AD, Sharafkhaneh A, et al. The asthma COPD overlap syndrome (ACOS). Curr Allergy Asthma Rep. 2015;15:509.
  • Elborn JS. The impact of personalised therapies on respiratory medicine. Eur Respir Rev. 2013;22:72–74.
  • Chung KF, Adcock IM. Clinical phenotypes of asthma should link up with disease mechanisms. Curr Opin Allergy Clin Immunol. 2015;15:56–62.
  • Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care2. J Allergy Clin Immunol. 2015;135:299–310.
  • Holgate ST. Stratified approaches to the treatment of asthma. Br J Clin Pharmacol. 2013;76:277–291.
  • Agustí A, Antó JM, Auffray C, et al. Personalized respiratory medicine: exploring the horizon, addressing the issues. Am J Respir Crit Care Med. 2015;191:391–401. Summary of a BRN-AJRCCM workshop held in Barcelona on June 12, 2014.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.