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DOI: 10.1055/s-0037-1606217
Airway Inflammation and Inflammatory Biomarkers
Publication History
Publication Date:
10 February 2018 (online)
![](https://www.thieme-connect.de/media/srccm/201801/lookinside/thumbnails/10-1055-s-0037-1606217_1334-1.jpg)
Abstract
Severe asthma is a complex disease consisting of different endotypes with different inflammatory and clinicopathological characteristics due to the heterogeneity of immune responses and smooth muscle dysfunction. There is an unmet clinical need to develop and to validate biomarkers that can differentiate between the asthma endotypes and guide clinical management, particularly since the availability of biologicals directed against T2 cytokines. The presence of a “Th2 endotype” is currently assessed in clinical practice using markers, such as eosinophil count in sputum or blood, fraction of exhaled nitric oxide, and immunoglobulin E. Individually or in combination, they may help to identify, for example, if the dominant effector protein is interleukin (IL) 5, IL13, or IgE. There is no reliable marker of a “non-Th2 endotype” although sputum neutrophil may provide some indication. The unbiased systems biology approach to severe asthma endotyping which integrates omics signatures and clinical data using large cohort studies may provide more comprehensive information than simple cellular measurements. Novel imaging techniques, such as hyperpolarized noble gas magnetic resonance imaging and computed tomography parametric response maps and metabolomics profiling in breath and other body fluids are also being evaluated as potential biomarkers to guide therapy and to assess prognosis.
Acknowledgment
Dr. Nair is supported by the Frederick E Hargreave Teva Innovation Chair in Airway Diseases.
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References
- 1 Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18 (05) 716-725
- 2 Lötvall J, Akdis CA, Bacharier LB. , et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127 (02) 355-360
- 3 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 (02) 343-373
- 4 Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol 2015; 135 (02) 299-310 , quiz 311
- 5 Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov 2012; 11 (12) 958-972
- 6 Rosi E, Ronchi MC, Grazzini M, Duranti R, Scano G. Sputum analysis, bronchial hyperresponsiveness, and airway function in asthma: results of a factor analysis. J Allergy Clin Immunol 1999; 103 (2 Pt 1): 232-237
- 7 Berry A, Busse WW. Biomarkers in asthmatic patients: Has their time come to direct treatment?. J Allergy Clin Immunol 2016; 137 (05) 1317-1324
- 8 Panganiban RP, Wang Y, Howrylak J. , et al. Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma. J Allergy Clin Immunol 2016; 137 (05) 1423-1432
- 9 Trivedi A, Hall C, Hoffman EA, Woods JC, Gierada DS, Castro M. Using imaging as a biomarker for asthma. J Allergy Clin Immunol 2017; 139 (01) 1-10
- 10 Siroux V, Boudier A, Dolgopoloff M. , et al. Forced midexpiratory flow between 25% and 75% of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes. J Allergy Clin Immunol 2016; 137 (06) 1709-1716.e6
- 11 Szefler SJ, Wenzel S, Brown R. , et al. Asthma outcomes: biomarkers. J Allergy Clin Immunol 2012; 129 (3, Suppl): S9-S23
- 12 Shaw DE, Sousa AR, Fowler SJ. , et al; U-BIOPRED Study Group. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 2015; 46 (05) 1308-1321
- 13 Loza MJ, Djukanovic R, Chung KF. , et al; ADEPT (Airways Disease Endotyping for Personalized Therapeutics) and U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) investigators. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res 2016; 17 (01) 165
- 14 Korevaar DA, Westerhof GA, Wang J. , 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 (04) 290-300
- 15 Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003; 167 (02) 199-204
- 16 Leckie MJ, ten Brinke A, Khan J. , et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356 (9248): 2144-2148
- 17 Belda J, Leigh R, Parameswaran K, O'Byrne PM, Sears MR, Hargreave FE. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med 2000; 161 (2 Pt 1): 475-478
- 18 Spanevello A, Confalonieri M, Sulotto F. , et al. Induced sputum cellularity. Reference values and distribution in normal volunteers. Am J Respir Crit Care Med 2000; 162 (3 Pt 1): 1172-1174
- 19 Meijer RJ, Postma DS, Kauffman HF, Arends LR, Koëter GH, Kerstjens HA. Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma. Clin Exp Allergy 2002; 32 (07) 1096-1103
- 20 Bacci E, Cianchetti S, Bartoli M. , et al. Low sputum eosinophils predict the lack of response to beclomethasone in symptomatic asthmatic patients. Chest 2006; 129 (03) 565-572
- 21 Calhoun WJ, Ameredes BT, King TS. , et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012; 308 (10) 987-997
- 22 Petsky HL, Cates CJ, Lasserson TJ. , et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67 (03) 199-208
- 23 Green RH, Brightling CE, McKenna S. , et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360 (9347): 1715-1721
- 24 Jayaram L, Pizzichini MM, Cook RJ. , et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27 (03) 483-494
- 25 Aziz-Ur-Rehman A, Dasgupta A, Kjarsgaard M, Hargreave FE, Nair P. Sputum cell counts to manage prednisone-dependent asthma: effects on FEV1 and eosinophilic exacerbations. Allergy Asthma Clin Immunol 2017; 13 (01) 17
- 26 Haldar P, Brightling CE, Hargadon B. , et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360 (10) 973-984
- 27 Nair P, Pizzichini MMM, Kjarsgaard M. , et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360 (10) 985-993
- 28 Nair P, Ochkur SI, Protheroe C. , et al. Eosinophil peroxidase in sputum represents a unique biomarker of airway eosinophilia. Allergy 2013; 68 (09) 1177-1184
- 29 Hu J, Wang S, Wang L. , et al. Advances in paper-based point-of-care diagnostics. Biosens Bioelectron 2014; 54: 585-597
- 30 Rank MA, Ochkur SI, Lewis JC. , et al. Nasal and pharyngeal eosinophil peroxidase levels in adults with poorly controlled asthma correlate with sputum eosinophilia. Allergy 2016; 71 (04) 567-570
- 31 Ortega HG, Liu MC, Pavord ID. , et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371 (13) 1198-1207
- 32 Bel EH, Wenzel SE, Thompson PJ. , et al; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371 (13) 1189-1197
- 33 FitzGerald JM, Bleecker ER, Nair P. , et al; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α 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): 2128-2141
- 34 Wenzel S, Castro M, Corren J. , et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388 (10039): 31-44
- 35 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 (04) 789-798
- 36 Nair P, O'Byrne PM. Measuring eosinophils to make treatment decisions in asthma. Chest 2016; 150 (03) 485-487
- 37 Mukherjee M, Nair P. Blood or sputum eosinophils to guide asthma therapy?. Lancet Respir Med 2015; 3 (11) 824-825
- 38 Sehmi R, Smith SG, Kjarsgaard M. , et al. Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma. Clin Exp Allergy 2016; 46 (06) 793-802
- 39 Smith SG, Chen R, Kjarsgaard M. , et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol 2016; 137 (01) 75-86.e8
- 40 Mukherjee M, Lim HF, Thomas S. , et al. Airway autoimmune responses in severe eosinophilic asthma following low-dose Mepolizumab therapy. Allergy Asthma Clin Immunol 2017; 13: 2
- 41 Dweik RA, Boggs PB, Erzurum SC. , et al; American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184 (05) 602-615
- 42 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) 1102-1108
- 43 Powell H, Murphy VE, Taylor DR. , et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011; 378 (9795): 983-990
- 44 Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016; 11: CD011439
- 45 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
- 46 Hanania NA, Wenzel S, Rosén 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 (08) 804-811
- 47 Corren J, Lemanske RF, Hanania NA. , et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365 (12) 1088-1098
- 48 Nair P, Kjarsgaard M, Armstrong S, Efthimiadis A, O'Byrne PM, Hargreave FE. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol 2010; 126 (02) 404-406
- 49 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 (09) 573-582
- 50 Hanania NA, Korenblat P, Chapman KR. , 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) 781-796
- 51 Wenzel S, Ford L, Pearlman D. , et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368 (26) 2455-2466
- 52 Kraft S, Kinet JP. New developments in FcepsilonRI regulation, function and inhibition. Nat Rev Immunol 2007; 7 (05) 365-378
- 53 Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 2012; 18 (05) 693-704
- 54 Humbert M, Beasley R, Ayres J. , et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60 (03) 309-316
- 55 Bousquet J, Cabrera P, Berkman N. , 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 (03) 302-308
- 56 Pillai P, Chan Y-C, Wu S-Y. , et al. Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J 2016; 48 (06) 1593-1601
- 57 Saini SS, Klion AD, Holland SM, Hamilton RG, Bochner BS, Macglashan Jr DW. The relationship between serum IgE and surface levels of FcepsilonR on human leukocytes in various diseases: correlation of expression with FcepsilonRI on basophils but not on monocytes or eosinophils. J Allergy Clin Immunol 2000; 106 (03) 514-520
- 58 Jia G, Erickson RW, Choy DF. , et al; Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) Study Group. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol 2012; 130 (03) 647-654.e10
- 59 Noonan M, Korenblat P, Mosesova S. , et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol 2013; 132 (03) 567-574.e12
- 60 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 (02) 115-120
- 61 Nicodemus-Johnson J, Naughton KA, Sudi J. , et al. Genome- wide methylation study identifies an IL-13-induced epigenetic signature in asthmatic airways. Am J Respir Crit Care Med 2016; 193 (04) 376-385
- 62 Chupp GL, Lee CG, Jarjour N. , et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 2007; 357 (20) 2016-2027
- 63 Tang H, Fang Z, Sun Y. , et al. YKL-40 in asthmatic patients, and its correlations with exacerbation, eosinophils and immunoglobulin E. Eur Respir J 2010; 35 (04) 757-760
- 64 Ober C, Tan Z, Sun Y. , et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med 2008; 358 (16) 1682-1691
- 65 Konradsen JR, James A, Nordlund B. , et al. The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma. J Allergy Clin Immunol 2013; 132 (02) 328-335.e5
- 66 James AJ, Reinius LE, Verhoek M. , et al; BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium. Increased YKL-40 and chitotriosidase in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2016; 193 (02) 131-142
- 67 Wedes SH, Wu W, Comhair SAA. , et al. Urinary bromotyrosine measures asthma control and predicts asthma exacerbations in children. J Pediatr 2011; 159 (02) 248-255.e1
- 68 Cowan DC, Taylor DR, Peterson LE. , et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015; 135 (04) 877-83.e1
- 69 Saude EJ, Skappak CD, Regush S. , et al. Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy. J Allergy Clin Immunol 2011; 127 (03) 757-764.e1 , 6
- 70 Adamko DJ, Nair P, Mayers I, Tsuyuki RT, Regush S, Rowe BH. Metabolomic profiling of asthma and chronic obstructive pulmonary disease: A pilot study differentiating diseases. J Allergy Clin Immunol 2015; 136 (03) 571-580.e3
- 71 Moore WC, Meyers DA, Wenzel SE. , et al; National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181 (04) 315-323
- 72 Haldar P, Pavord ID, Shaw DE. , et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178 (03) 218-224
- 73 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 (05) 388-395
- 74 Lefaudeux D, De Meulder B, Loza MJ. , et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics. J Allergy Clin Immunol 2017; 139: 1797-1807
- 75 Wilson SJ, Ward JA, Sousa AR. , et al; U-BIOPRED Study Group. Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study. Eur Respir J 2016; 48 (05) 1307-1319
- 76 Kuo CS, Pavlidis S, Loza M. , et al; U-BIOPRED Project Team ‡. A Transcriptome- driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED. Am J Respir Crit Care Med 2017; 195 (04) 443-455
- 77 Kuo CS, Pavlidis S, Loza M. , et al; U-BIOPRED Study Group. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J 2017; 49 (02) 1602135
- 78 Bigler J, Boedigheimer M, Schofield JPR. , et al; U-BIOPRED Study Group P. A Severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts. Am J Respir Crit Care Med 2017; 195 (10) 1311-1320
- 79 Carraro S, Rezzi S, Reniero F. , et al. Metabolomics applied to exhaled breath condensate in childhood asthma. Am J Respir Crit Care Med 2007; 175 (10) 986-990
- 80 Svenningsen S, Nair P, Guo F, McCormack DG, Parraga G. Is ventilation heterogeneity related to asthma control?. Eur Respir J 2016; 48 (02) 370-379
- 81 Thomen RP, Sheshadri A, Quirk JD. , et al. Regional ventilation changes in severe asthma after bronchial thermoplasty with (3)He MR imaging and CT. Radiology 2015; 274 (01) 250-259
- 82 Moore WC, Hastie AT, Li X. , et al; National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol 2014; 133 (06) 1557-1563.e5
- 83 Mukherjee M, Svenningsen S, Nair P. Glucocortiosteroid subsensitivity and asthma severity. Curr Opin Pulm Med 2017; 23 (01) 78-88
- 84 Nadif R, Siroux V, Boudier A. , et al. Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study. Eur Respir J 2016; 48 (04) 1040-1051
- 85 Goleva E, Jackson LP, Gleason M, Leung DY. Usefulness of PBMCs to predict clinical response to corticosteroids in asthmatic patients. J Allergy Clin Immunol 2012; 129 (03) 687-693.e1
- 86 Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest 2012; 142 (01) 86-93
- 87 Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax 2010; 65 (05) 384-390
- 88 Chesné 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) 1094-1101
- 89 Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J 2014; 43 (04) 1067-1076
- 90 Busse WW, Holgate S, Kerwin E. , 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) 1294-1302
- 91 O'Byrne PM, Metev H, Puu 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