Biomarkers in the Management of Difficult Asthma.

[en] Difficult asthma is a heterogeneous disease of the airways including various types of bronchial inflammation and various degrees of airway remodeling. Therapeutic response of severe asthmatics can be predicted by the use of biomarkers of Type2-high or Type2-low inflammation. Based on sputum cell analysis, four inflammatory phenotypes have been described. As induced sputum is timeconsuming and expensive technique, surrogate biomarkers are useful in clinical practice. Eosinophilic phenotype is likely to reflect ongoing adaptive immunity in response to allergen. Several biomarkers of eosinophilic asthma are easily available in clinical practice (blood eosinophils, serum IgE, exhaled nitric oxyde, serum periostin). Neutrophilic asthma is thought to reflect innate immune system activation in response to pollutants or infectious agents while paucigranulocytic asthma is thought to be not inflammatory and characterized by smooth muscle dysfunction. We currently lack of user-friendly biomarkers of neutrophilic asthma and airway remodeling. In this review, we summarize the biomarkers available for the management of difficult asthma.

Disciplines :

Cardiovascular & respiratory systems

Author, co-author :

Schleich, Florence ; Université de Liège - ULiège > Département des sciences de la motricité > Département des sciences de la motricité

Demarche, Sophie

Louis, Renaud ; Université de Liège - ULiège > Département des sciences cliniques > Pneumologie - Allergologie

Language :

English

Title :

Biomarkers in the Management of Difficult Asthma.

Publication date :

2016

Journal title :

Current Topics in Medicinal Chemistry

ISSN :

1568-0266

eISSN :

1873-4294

Publisher :

Bentham Science Publishers, United Arab Emirates

Volume :

Issue :

Pages :

1561-73

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 11 December 2020

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3 (3 by ULiège)

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Bibliography

[1] Bel, E. H.; Sousa, A.; Fleming, L.; Bush, A.; Chung, K. F.; Versnel, J.; Wagener, A. H.; Wagers, S. S.; Sterk, P. J.; Compton, C. H. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax, 2011, 66, 910-917.
[2] Chung, K. F.; Wenzel, S. E.; Brozek, J. L.; Bush, A.; Castro, M.; Sterk, P. J.; Adcock, I. M.; Bateman, E. D.; Bel, E. H.; Bleecker, E. R.; Boulet, L. P.; Brightling, C.; Chanez, P.; Dahlen, S. E.; Djukanovic, R.; Frey, U.; Gaga, M.; Gibson, P.; Hamid, Q.; Jajour, N. N.; Mauad, T.; Sorkness, R. L.; Teague, W. G. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J., 2014, 43, 343-373.
[3] Simpson, J. L.; Scott, R.; Boyle, M. J.; Gibson, P. G. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology, 2006, 11, 54-61.
[4] Licona-Limon, P.; Kim, L. K.; Palm, N. W.; Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol., 2013, 14, 536-542.
[5] Anderson, G. P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet, 2008, 372, 1107-1119.
[6] Douwes, J.; Gibson, P.; Pekkanen, J.; Pearce, N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax, 2002, 57, 643-648.
[7] Fahy, J. V.; Boushey, H. A. Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation. Eur. Respir. J., 1998, 11, 1240-1247.
[8] van Rensen, E. L.; Straathof, K. C.; Veselic-Charvat, M. A.; Zwinderman, A. H.; Bel, E. H.; Sterk, P. J. Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax, 1999, 54, 403-408.
[9] Corrigan, C. J.; Haczku, A.; Gemou-Engesaeth, V.; Doi, S.; Kikuchi, Y.; Takatsu, K.; Durham, S. R.; Kay, A. B. CD4 Tlymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Effect of glucocorticoid therapy. Am. Rev. Respir. Dis., 1993, 147, 540-547.
[10] Lilly, C. M.; Nakamura, H.; Kesselman, H.; Nagler-Anderson, C.; Asano, K.; Garcia-Zepeda, E. A.; Rothenberg, M. E.; Drazen, J. M.; Luster, A. D. Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J. Clin. Invest., 1997, 99, 1767-1773.
[11] Green, R. H.; Brightling, C. E.; McKenna, S.; Hargadon, B.; Parker, D.; Bradding, P.; Wardlaw, A. J.; Pavord, I. D. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet, 2002, 360, 1715-1721.
[12] Jayaram, L.; Pizzichini, M. M.; Cook, R. J.; Boulet, L. P.; Lemiere, C.; Pizzichini, E.; Cartier, A.; Hussack, P.; Goldsmith, C. H.; Laviolette, M.; Parameswaran, K.; Hargreave, F. E. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur. Respir. J., 2006, 27, 483-494.
[13] Louis, R.; Lau, L. C.; Bron, A. O.; Roldaan, A. C.; Radermecker, M.; Djukanovic, R. The relationship between airways inflammation and asthma severity. Am. J. Respir. Crit. Care Med., 2000, 161, 9-16.
[14] Duncan, C. J.; Lawrie, A.; Blaylock, M. G.; Douglas, J. G.; Walsh, G. M. Reduced eosinophil apoptosis in induced sputum correlates with asthma severity. Eur. Respir. J., 2003, 22, 484-490.
[15] Schleich, F.; Brusselle, G.; Louis, R.; Vandenplas, O.; Michils, A.; Pilette, C.; Peche, R.; Manise, M.; Joos, G. Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR). Respir. Med., 2014, 108, 1723-1732.
[16] Haldar, P.; Pavord, I. D.; Shaw, D. E.; Berry, M. A.; Thomas, M.; Brightling, C. E.; Wardlaw, A. J.; Green, R. H. Cluster analysis and clinical asthma phenotypes. Am.J.Respir.Crit. Care Med., 2008, 178, 218-224.
[17] Schleich, F. N.; Chevremont, A.; Paulus, V.; Henket, M.; Manise, M.; Seidel, L.; Louis, R. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur. Respir. J., 2014, 44, 97-108.
[18] Wardlaw, A. J.; Dunnette, S.; Gleich, G. J.; Collins, J. V.; Kay, A. B. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am.Rev.Respir.Dis., 1988, 137, 62-69.
[19] Sont, J. K.; Han, J.; van Krieken, J. M.; Evertse, C. E.; Hooijer, R.; Willems, L. N.; Sterk, P. J. Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids. Thorax, 1996, 51, 496-502.
[20] Volbeda, F.; Broekema, M.; Lodewijk, M. E.; Hylkema, M. N.; Reddel, H. K.; Timens, W.; Postma, D. S.; Ten Hacken, N. H. Clinical control of asthma associates with measures of airway inflammation. Thorax, 2013, 68, 19-24.
[21] Deykin, A.; Lazarus, S. C.; Fahy, J. V.; Wechsler, M. E.; Boushey, H. A.; Chinchilli, V. M.; Craig, T. J.; Dimango, E.; Kraft, M.; Leone, F.; Lemanske, R. F.; Martin, R. J.; Pesola, G. R.; Peters, S. P.; Sorkness, C. A.; Szefler, S. J.; Israel, E. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J.Allergy Clin.Immunol., 2005, 115, 720-727.
[22] Jatakanon, A.; Lim, S.; Barnes, P. J. Changes in sputum eosinophils predict loss of asthma control. Am. J. Respir. Crit. Care Med., 2000, 161, 64-72.
[23] Munoz, X.; Sanchez-Vidaurre, S.; Roca, O.; Torres, F.; Morell, F.; Cruz, M. J. Bronchial inflammation and hyperresponsiveness in well controlled asthma. Clin. Exp. Allergy, 2012, 42, 1321-1328.
[24] Schleich, F. N.; Seidel, L.; Sele, J.; Manise, M.; Quaedvlieg, V.; Michils, A.; Louis, R. Exhaled nitric oxide thresholds associated with a sputum eosinophil count >/=3% in a cohort of unselected patients with asthma. Thorax, 2010, 65, 1039-1044.
[25] Hansel, T. T.; Kharitonov, S. A.; Donnelly, L. E.; Erin, E. M.; Currie, M. G.; Moore, W. M.; Manning, P. T.; Recker, D. P.; Barnes, P. J. A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics. FASEB J., 2003, 17, 1298-1300.
[26] Chibana, K.; Trudeau, J. B.; Mustovich, A. T.; Hu, H.; Zhao, J.; Balzar, S.; Chu, H. W.; Wenzel, S. E. IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clin.Exp.Allergy, 2008, 38, 936-946.
[27] Jatakanon, A.; Kharitonov, S.; Lim, S.; Barnes, P. J. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax, 1999, 54, 108-114.
[28] Pavord, I. D. Asthma control, airway responsiveness and airway inflammation. Clin. Exp. Allergy, 2009, 39, 1780-1782.
[29] Haldar, P.; Brightling, C. E.; Hargadon, B.; Gupta, S.; Monteiro, W.; Sousa, A.; Marshall, R. P.; Bradding, P.; Green, R. H.; Wardlaw, A. J.; Pavord, I. D. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med., 2009, 360, 973-984.
[30] Wagener, A. H.; de Nijs, S. B.; Lutter, R.; Sousa, A. R.; Weersink, E. J.; Bel, E. H.; Sterk, P. J. External validation of blood eosinophils, FENO and serum periostin as surrogates for sputum eosinophils in asthma. Thorax, 2015, 70, 115-120.
[31] Cowan, D. C.; Taylor, D. R.; Peterson, L. E.; Cowan, J. O.; Palmay, R.; Williamson, A.; Hammel, J.; Erzurum, S. C.; Hazen, S. L.; Comhair, S. A. Biomarker-based asthma phenotypes of corticosteroid response. J. Allergy Clin. Immunol., 2014, 135(4), 877-83
[32] Hanania, N. A.; Wenzel, S.; Rosen, K.; Hsieh, H. J.; Mosesova, S.; Choy, D. F.; Lal, P.; Arron, J. R.; Harris, J. M.; Busse, W. 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.
[33] Humbert, M.; Busse, W.; Hanania, N. A.; Lowe, P. J.; Canvin, J.; Erpenbeck, V. J.; Holgate, S. Omalizumab in asthma: an update on recent developments. J. Allergy Clin. Immunol. Pract., 2014, 2, 525-536.
[34] Corren, J.; Lemanske, R. F.; Hanania, N. A.; Korenblat, P. E.; Parsey, M. V.; Arron, J. R.; Harris, J. M.; Scheerens, H.; Wu, L. C.; Su, Z.; Mosesova, S.; Eisner, M. D.; Bohen, S. P.; Matthews, J. G. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med., 2011, 365, 1088-1098.
[35] Nair, P.; Pizzichini, M. M.; Kjarsgaard, M.; Inman, M. D.; Efthimiadis, A.; Pizzichini, E.; Hargreave, F. E.; O'Byrne, P. M. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med., 2009, 360, 985-993.
[36] Pavord, I. D.; Korn, S.; Howarth, P.; Bleecker, E. R.; Buhl, R.; Keene, O. N.; Ortega, H.; Chanez, P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet, 2012, 380, 651-659.
[37] Nadif, R.; Siroux, V.; Oryszczyn, M. P.; Ravault, C.; Pison, C.; Pin, I.; Kauffmann, F. Heterogeneity of asthma according to blood inflammatory patterns. Thorax, 2009, 64, 374-380.
[38] Hastie, A. T.; Moore, W. C.; Meyers, D. A.; Vestal, P. L.; Li, H.; Peters, S. P.; Bleecker, E. R. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J. Allergy Clin. Immunol., 2010, 125, 1028-1036.
[39] Busse, W.; Spector, S.; Rosen, K.; Wang, Y.; Alpan, O. High eosinophil count: a potential biomarker for assessing successfulomalizumab treatment effects. J. Allergy Clin. Immunol., 2013, 132, 485-486.
[40] Woodruff, P. G.; Modrek, B.; Choy, D. F.; Jia, G.; Abbas, A. R.; Ellwanger, A.; Koth, L. L.; Arron, J. R.; Fahy, J. V. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med., 2009, 180, 388-395.
[41] Jia, G.; Erickson, R. W.; Choy, D. F.; Mosesova, S.; Wu, L. C.; Solberg, O. D.; Shikotra, A.; Carter, R.; Audusseau, S.; Hamid, Q.; Bradding, P.; Fahy, J. V.; Woodruff, P. G.; Harris, J. M.; Arron, J. R. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J. Allergy Clin. Immunol., 2012, 130, 647-654.
[42] Woodruff, P. G.; Boushey, H. A.; Dolganov, G. M.; Barker, C. S.; Yang, Y. H.; Donnelly, S.; Ellwanger, A.; Sidhu, S. S.; Dao-Pick, T. P.; Pantoja, C.; Erle, D. J.; Yamamoto, K. R.; Fahy, J. V. 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.
[43] Louis, R.; Shute, J.; Biagi, S.; Stanciu, L.; Marrelli, F.; Tenor, H.; Hidi, R.; Djukanovic, R. Cell infiltration, ICAM-1 expression, and eosinophil chemotactic activity in asthmatic sputum. Am. J. Respir. Crit. Care Med., 1997, 155, 466-472.
[44] Dente, F. L.; Carnevali, S.; Bartoli, M. L.; Cianchetti, S.; Bacci, E.; Di, Franco A.; Vagaggini, B.; Paggiaro, P. Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients. Ann. Allergy Asthma Immunol., 2006, 97, 312-320.
[45] Pizzichini, E.; Pizzichini, M. M.; Efthimiadis, A.; Evans, S.; Morris, M. M.; Squillace, D.; Gleich, G. J.; Dolovich, J.; Hargreave, F. E. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am. J. Respir. Crit. Care Med., 1996, 154, 308-317.
[46] Keatings, V. M.; Barnes, P. J. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am. J. Respir. Crit. Care Med., 1997, 155, 449-453.
Manise, M.; Holtappels, G.; Van, Crombruggen K.; Schleich, F.; Bachert, C.; Louis, R. Sputum IgE and cytokines in asthma: relationship with sputum cellular profile. PLoS One., 2013, 8, e58388-
[48] Tseliou, E.; Bakakos, P.; Kostikas, K.; Hillas, G.; Mantzouranis, K.; Emmanouil, P.; Simoes, D.; Alchanatis, M.; Papiris, S.; Loukides, S. Increased levels of angiopoietins 1 and 2 in sputum supernatant in severe refractory asthma. Allergy, 2012, 67, 396-402.
[49] Delimpoura, V.; Bakakos, P.; Tseliou, E.; Bessa, V.; Hillas, G.; Simoes, D. C.; Papiris, S.; Loukides, S. Increased levels of osteopontin in sputum supernatant in severe refractory asthma. Thorax, 2010, 65, 782-786.
[50] Dente, F. L.; Carnevali, S.; Bartoli, M. L.; Cianchetti, S.; Bacci, E.; Di, Franco A.; Vagaggini, B.; Paggiaro, P. Profiles of proinflammatory cytokines in sputum from different groups of severe asthmatic patients. Ann. Allergy Asthma Immunol., 2006, 97, 312-320.
[51] Quaedvlieg, V.; Sele, J.; Henket, M.; Louis, R. Association between asthma control and bronchial hyperresponsiveness and airways inflammation: a cross-sectional study in daily practice. Clin. Exp. Allergy, 2009, 39, 1822-1829.
[52] Jang, A. S.; Choi, I. S.; Lee, S.; Seo, J. P.; Yang, S. W.; Park, K. O.; Lee, K. Y.; Lee, J. U.; Park, C. S.; Park, H. S. Nitric oxide metabolites in induced sputum: a marker of airway inflammation in asthmatic subjects. Clin. Exp. Allergy, 1999, 29, 1136-1142.
[53] Paredi, P.; Kharitonov, S. A.; Barnes, P. J. Elevation of exhaled ethane concentration in asthma. Am. J. Respir. Crit. Care Med., 2000, 162, 1450-1454.
[54] Ibrahim, B.; Basanta, M.; Cadden, P.; Singh, D.; Douce, D.; Woodcock, A.; Fowler, S. J. Non-invasive phenotyping using exhaled volatile organic compounds in asthma. Thorax, 2011, 66, 804-809.
[55] Hanania, N. A.; Alpan, O.; Hamilos, D. L.; Condemi, J. J.; Reyes-Rivera, I.; Zhu, J.; Rosen, K. E.; Eisner, M. D.; Wong, D. A.; Busse, W. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann. Intern. Med., 2011, 154, 573-582.
[56] Humbert, M.; Beasley, R.; Ayres, J.; Slavin, R.; Hebert, J.; Bousquet, J.; Beeh, K. M.; Ramos, S.; Canonica, G. W.; Hedgecock, S.; Fox, H.; Blogg, M.; Surrey, K. 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, 309-316.
[57] Louis, R. Anti-IgE: a significant breakthrough in the treatment of airway allergic diseases. Allergy, 2004, 59, 698-700.
[58] Castro, M.; Mathur, S.; Hargreave, F.; Boulet, L. P.; Xie, F.; Young, J.; Wilkins, H. J.; Henkel, T.; Nair, P. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebocontrolled study. Am. J. Respir.Crit. Care Med., 2011, 184, 1125-1132.
[59] De Boever, E. H.; Ashman, C.; Cahn, A. P.; Locantore, N. W.; Overend, P.; Pouliquen, I. J.; Serone, A. P.; Wright, T. J.; Jenkins, M. M.; Panesar, I. S.; Thiagarajah, S. S.; Wenzel, S. E. Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial. J. Allergy Clin. Immunol., 2014, 133, 989-996.
[60] Piper, E.; Brightling, C.; Niven, R.; Oh, C.; Faggioni, R.; Poon, K.; She, D.; Kell, C.; May, R. D.; Geba, G. P.; Molfino, N. A. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur. Respir. J., 2013, 41, 330-338.
[61] Hanania, N. A.; Noonan, M.; Corren, J.; Korenblat, P.; Zheng, Y.; Fischer, S. K.; Cheu, M.; Putnam, W. S.; Murray, E.; Scheerens, H.; Holweg, C. T.; Maciuca, R.; Gray, S.; Doyle, R.; McClintock, D.; Olsson, J.; Matthews, J. G.; Yen, K. Lebrikizumab in moderateto-severe asthma: pooled data from two randomised placebocontrolled studies. Thorax, 2015, doi:10.1136/thoraxjnl-2014-206719
[62] Gauvreau, G. M.; Boulet, L. P.; Cockcroft, D. W.; Fitzgerald, J. M.; Carlsten, C.; Davis, B. E.; Deschesnes, F.; Duong, M.; Durn, B. L.; Howie, K. J.; Hui, L.; Kasaian, M. T.; Killian, K. J.; Strinich, T. X.; Watson, R. M.; Y N Zhou, S.; Raible, D.; O'Byrne, P. M. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am. J. Respir. Crit. Care Med., 2011, 183, 1007-1014.
[63] Wenzel, S.; Wilbraham, D.; Fuller, R.; Getz, E. B.; Longphre, M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet, 2007, 370, 1422-1431.
[64] Slager, R. E.; Otulana, B. A.; Hawkins, G. A.; Yen, Y. P.; Peters, S. P.; Wenzel, S. E.; Meyers, D. A.; Bleecker, E. R. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor alpha antagonist. J. Allergy Clin. Immunol., 2012, 130, 516-522.
[65] Wenzel, S.; Ford, L.; Pearlman, D.; Spector, S.; Sher, L.; Skobieranda, F.; Wang, L.; Kirkesseli, S.; Rocklin, R.; Bock, B.; Hamilton, J.; Ming, J. E.; Radin, A.; Stahl, N.; Yancopoulos, G. D.; Graham, N.; Pirozzi, G. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med., 2013, 368, 2455-2466.
[66] Wenzel, S. E.; Schwartz, L. B.; Langmack, E. L.; Halliday, J. L.; Trudeau, J. B.; Gibbs, R. L.; Chu, H. W. 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.
[67] Haldar, P.; Pavord, I. D. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J. Allergy Clin. Immunol., 2007, 119, 1043-1052.
[68] The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur. Respir. J., 2003, 22, 470-477.
[69] Jatakanon, A.; Uasuf, C.; Maziak, W.; Lim, S.; Chung, K. F.; Barnes, P. J. Neutrophilic inflammation in severe persistent asthma. Am. J. Respir. Crit. Care Med., 1999, 160, 1532-1539.
[70] Kamath, A. V.; Pavord, I. D.; Ruparelia, P. R.; Chilvers, E. R. Is the neutrophil the key effector cell in severe asthma? Thorax, 2005, 60, 529-530.
[71] Little, S. A.; MacLeod, K. J.; Chalmers, G. W.; Love, J. G.; McSharry, C.; Thomson, N. C. Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma. Am. J. Med., 2002, 112, 446-452.
[72] Shaw, D. E.; Berry, M. A.; Hargadon, B.; McKenna, S.; Shelley, M. J.; Green, R. H.; Brightling, C. E.; Wardlaw, A. J.; Pavord, I. D. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest, 2007, 132, 1871-1875.
Schleich, F. N.; Manise, M.; Sele, J.; Henket, M.; Seidel, L.; Louis, R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC. Pulm. Med., 2013, 13, 11-
Louis, R.; Godinas, L.; Schleich, F. Induced Sputum-Towards Normal Values. Paschalidis Medical Publications, 2011, pp: 113-123.
[75] Vuola, J. M.; Puurula, V.; Anttila, M.; Makela, P. H.; Rautonen, N. Acquired immunity to Chlamydia pneumoniae is dependent on gamma interferon in two mouse strains that initially differ in this respect after primary challenge. Infect. Immun., 2000, 68, 960-964.
[76] Zhou, X.; Chen, Q.; Moore, J.; Kolls, J. K.; Halperin, S.; Wang, J. Critical role of the interleukin-17/interleukin-17 receptor axis in regulating host susceptibility to respiratory infection with Chlamydia species. Infect. Immun., 2009, 77, 5059-5070.
Essilfie, A. T.; Simpson, J. L.; Horvat, J. C.; Preston, J. A.; Dunkley, M. L.; Foster, P. S.; Gibson, P. G.; Hansbro, P. M. Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease. PLoS Pathog., 2011, 7, e1002244-
[78] Simpson, J. L.; Grissell, T. V.; Douwes, J.; Scott, R. J.; Boyle, M. J.; Gibson, P. G. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax, 2007, 62, 211-218.
[79] Wood, L. G.; Baines, K. J.; Fu, J.; Scott, H. A.; Gibson, P. G. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest, 2012, 142, 86-93.
[80] Baggiolini, M.; Walz, A.; Kunkel, S. L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J. Clin. Invest., 1989, 84, 1045-1049.
[81] Gibson, P. G.; Simpson, J. L.; Saltos, N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest, 2001, 119, 1329-1336.
Leaker, B. R.; Barnes, P. J.; O'Connor, B. Inhibition of LPSinduced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. Respir. Res., 2013, 14, 137-
[83] Nair, P.; Gaga, M.; Zervas, E.; Alagha, K.; Hargreave, F. E.; O'Byrne, P. M.; Stryszak, P.; Gann, L.; Sadeh, J.; Chanez, P. 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.
[84] Al-Ramli, W.; Prefontaine, D.; Chouiali, F.; Martin, J. G.; Olivenstein, R.; Lemiere, C.; Hamid, Q. T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J. Allergy Clin. Immunol., 2009, 123, 1185-1187.
[85] Linden, A. Role of interleukin-17 and the neutrophil in asthma. Int. Arch. Allergy Immunol., 2001, 126, 179-184.
Bullens, D. M.; Truyen, E.; Coteur, L.; Dilissen, E.; Hellings, P. W.; Dupont, L. J.; Ceuppens, J. L. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir. Res., 2006, 7, 135-
[87] Berry, M. A.; Hargadon, B.; Shelley, M.; Parker, D.; Shaw, D. E.; Green, R. H.; Bradding, P.; Brightling, C. E.; Wardlaw, A. J.; Pavord, I. D. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med., 2006, 354, 697-708.
[88] Brightling, C.; Berry, M.; Amrani, Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J. Allergy Clin. Immunol., 2008, 121, 5-10.
[89] Thomas, P. S. and Heywood, G. Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax, 2002, 57, 774-778.
[90] Simpson, J. L.; Scott, R. J.; Boyle, M. J.; Gibson, P. G. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma. Am. J. Respir. Crit. Care Med., 2005, 172, 559-565.
Green, B. J.; Wiriyachaiporn, S.; Grainge, C.; Rogers, G. B.; Kehagia, V.; Lau, L.; Carroll, M. P.; Bruce, K. D.; Howarth, P. H. Potentially pathogenic airway bacteria and neutrophilic inflammation in treatment resistant severe asthma. PLoS One, 2014, 9, e100645-
[92] Kuipers, I.; Louis, R.; Manise, M.; Dentener, M. A.; Irvin, C. G.; Janssen-Heininger, Y. M.; Brightling, C. E.; Wouters, E. F.; Reynaert, N. L. Increased glutaredoxin-1 and decreased protein Sglutathionylation in sputum of asthmatics. Eur. Respir. J., 2013, 41, 469-472.
[93] Green, R. H.; Brightling, C. E.; Woltmann, G.; Parker, D.; Wardlaw, A. J.; Pavord, I. D. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax, 2002, 57, 875-879.
[94] Louis, R. and Djukanovic, R. Is the neutrophil a worthy target in severe asthma and chronic obstructive pulmonary disease? Clin. Exp. Allergy, 2006, 36, 563-567.
[95] Brusselle, G. G. and Joos, G. Is there a role for macrolides in severe asthma? Curr. Opin. Pulm. Med., 2014, 20, 95-102.
[96] Simpson, J. L.; Powell, H.; Boyle, M. J.; Scott, R. J.; Gibson, P. G. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am. J. Respir. Crit. Care Med., 2008, 177, 148-155.
[97] Sutherland, E. R.; King, T. S.; Icitovic, N.; Ameredes, B. T.; Bleecker, E.; Boushey, H. A.; Calhoun, W. J.; Castro, M.; Cherniack, R. M.; Chinchilli, V. M.; Craig, T. J.; Denlinger, L.; Dimango, E. A.; Fahy, J. V.; Israel, E.; Jarjour, N.; Kraft, M.; Lazarus, S. C.; Lemanske, Jr. R. F.;; Peters, S. P.; Ramsdell, J.; Sorkness, C. A.; Szefler, S. J.; Walter, M. J.; Wasserman, S. I.; Wechsler, M. E.; Chu, H. W.; Martin, R. J. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J. Allergy Clin. Immunol., 2010, 126, 747-753.
[98] Brusselle, G. G.; Vanderstichele, C.; Jordens, P.; Deman, R.; Slabbynck, H.; Ringoet, V.; Verleden, G.; Demedts, I. K.; Verhamme, K.; Delporte, A.; Demeyere, B.; Claeys, G.; Boelens, J.; Padalko, E.; Verschakelen, J.; Van, Maele G.; Deschepper, E.; Joos, G. F. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax, 2013, 68, 322-329.
[99] Travers, J.; Marsh, S.; Aldington, S.; Williams, M.; Shirtcliffe, P.; Pritchard, A.; Weatherall, M.; Beasley, R. Reference ranges for exhaled nitric oxide derived from a random community survey of adults. Am. J. Respir. Crit. Care Med., 2007, 176, 238-242.
[100] Gibson, P. G. Macrolides for yet another chronic airway disease: severe asthma? Thorax, 2013, 68, 313-314.
[101] Busse, W. W.; Holgate, S.; Kerwin, E.; Chon, Y.; Feng, J.; Lin, J.; Lin, S. L. 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, 1294-1302.
[102] Morjaria, J. B.; Chauhan, A. J.; Babu, K. S.; Polosa, R.; Davies, D. E.; Holgate, S. T. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax, 2008, 63, 584-591.
[103] Wenzel, S. E.; Barnes, P. J.; Bleecker, E. R.; Bousquet, J.; Busse, W.; Dahlen, S. E.; Holgate, S. T.; Meyers, D. A.; Rabe, K. F.; Antczak, A.; Baker, J.; Horvath, I.; Mark, Z.; Bernstein, D.; Kerwin, E.; Schlenker-Herceg, R.; Lo, K. H.; Watt, R.; Barnathan, E. S.; Chanez, P. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med., 2009, 179, 549-558.
[104] Holgate, S. T.; Noonan, M.; Chanez, P.; Busse, W.; Dupont, L.; Pavord, I.; Hakulinen, A.; Paolozzi, L.; Wajdula, J.; Zang, C.; Nelson, H.; Raible, D. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur. Respir. J., 2011, 37, 1352-1359.
[105] Barnes, P. J. Severe asthma: advances in current management and future therapy. J. Allergy Clin. Immunol., 2012, 129, 48-59.
[106] Beghe, B.; Rabe, K. F.; Fabbri, L. M. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am. J. Respir. Crit. Care Med., 2013, 188, 271-278.
[107] Wenzel, S. E. Asthma: defining of the persistent adult phenotypes. Lancet, 2006, 368, 804-813.
[108] Benayoun, L.; Druilhe, A.; Dombret, M. C.; Aubier, M.; Pretolani, M. Airway structural alterations selectively associated with severe asthma. Am. J. Respir. Crit. Care Med., 2003, 167, 1360-1368.
[109] Little, S. A.; Sproule, M. W.; Cowan, M. D.; MacLeod, K. J.; Robertson, M.; Love, J. G.; Chalmers, G. W.; McSharry, C. P.; Thomson, N. C. High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity. Thorax, 2002, 57, 247-253.
[110] Gupta, S.; Siddiqui, S.; Haldar, P.; Raj, J. V.; Entwisle, J. J.; Wardlaw, A. J.; Bradding, P.; Pavord, I. D.; Green, R. H.; Brightling, C. E. Qualitative analysis of high-resolution CT scans in severe asthma. Chest, 2009, 136, 1521-1528.
[111] Vignola, A. M.; Riccobono, L.; Mirabella, A.; Profita, M.; Chanez, P.; Bellia, V.; Mautino, G.; D'accardi, P.; Bousquet, J.; Bonsignore, G. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med., 1998, 158, 1945-1950.
[112] Vignola, A. M.; Paganin, F.; Capieu, L.; Scichilone, N.; Bellia, M.; Maakel, L.; Bellia, V.; Godard, P.; Bousquet, J.; Chanez, P. Airway remodelling assessed by sputum and high-resolution computed tomography in asthma and COPD. Eur. Respir. J., 2004, 24, 910-917.
[113] Bissonnette, E. Y.; Madore, A. M.; Chakir, J.; Laviolette, M.; Boulet, L. P.; Hamid, Q.; Bergeron, C.; Maghni, K.; Laprise, C. Fibroblast growth factor-2 is a sputum remodeling biomarker of severe asthma. J. Asthma, 2014, 51, 119-126.
[114] Mauri, P.; Riccio, A. M.; Rossi, R.; Di, Silvestre D.; Benazzi, L.; De, Ferrari L.; Dal Negro, R. W.; Holgate, S. T.; Canonica, G. W. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumabtreated severe asthma patients. Immunol. Lett., 2014, 162, 2-10.
[115] Shaker, S. B.; von Wachenfeldt, K. A.; Larsson, S.; Mile, I.; Persdotter, S.; Dahlback, M.; Broberg, P.; Stoel, B.; Bach, K. S.; Hestad, M.; Fehniger, T. E.; Dirksen, A. Identification of patients with chronic obstructive pulmonary disease (COPD) by measurement of plasma biomarkers. Clin. Respir. J., 2008, 2, 17-25.
[116] Bourdin, A.; Kotsimbos, T.; Nguyen, K.; Vachier, I.; Mainprice, B.; Farce, M.; Paganin, F.; Marty-Ane, C.; Vernhet, H.; Godard, P.; Chanez, P. Non-invasive assessment of small airway remodelling in smokers. COPD., 2010, 7, 102-110.
[117] Bonella, F. and Costabel, U. Biomarkers in connective tissue disease-associated interstitial lung disease. Semin. Respir. Crit. Care Med., 2014, 35, 181-200.
[118] James, A. L.; Palmer, L. J.; Kicic, E.; Maxwell, P. S.; Lagan, S. E.; Ryan, G. F.; Musk, A. W. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am. J. Respir. Crit. Care Med., 2005, 171, 109-114.
[119] van Veen, I. H.; ten Brinke, A.; Sterk, P. J.; Sont, J. K.; Gauw, S. A.; Rabe, K. F.; Bel, E. H. Exhaled nitric oxide predicts lung function decline in difficult-to-treat asthma. Eur. Respir. J., 2008, 32, 344-349.
[120] Contoli, M.; Baraldo, S.; Marku, B.; Casolari, P.; Marwick, J. A.; Turato, G.; Romagnoli, M.; Caramori, G.; Saetta, M.; Fabbri, L. M.; Papi, A. Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up. J. Allergy Clin. Immunol., 2010, 125, 830-837.
[121] Jongepier, H.; Boezen, H. M.; Dijkstra, A.; Howard, T. D.; Vonk, J. M.; Koppelman, G. H.; Zheng, S. L.; Meyers, D. A.; Bleecker, E. R.; Postma, D. S. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin. Exp. Allergy, 2004, 34, 757-760.
[122] Dijkstra, A.; Howard, T. D.; Vonk, J. M.; Ampleford, E. J.; Lange, L. A.; Bleecker, E. R.; Meyers, D. A.; Postma, D. S. Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma. J. Allergy Clin. Immunol., 2006, 117, 604-611.
[123] Barton, S. J.; Koppelman, G. H.; Vonk, J. M.; Browning, C. A.; Nolte, I. M.; Stewart, C. E.; Bainbridge, S.; Mutch, S.; Rose-Zerilli, M. J.; Postma, D. S.; Maniatis, N.; Henry, A. P.; Hall, I. P.; Holgate, S. T.; Tighe, P.; Holloway, J. W.; Sayers, I. PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline. J. Allergy Clin. Immunol., 2009, 123, 1391-1400.
[124] Kanemitsu, Y.; Matsumoto, H.; Izuhara, K.; Tohda, Y.; Kita, H.; Horiguchi, T.; Kuwabara, K.; Tomii, K.; Otsuka, K.; Fujimura, M.; Ohkura, N.; Tomita, K.; Yokoyama, A.; Ohnishi, H.; Nakano, Y.; Oguma, T.; Hozawa, S.; Nagasaki, T.; Ito, I.; Oguma, T.; Inoue, H.; Tajiri, T.; Iwata, T.; Izuhara, Y.; Ono, J.; Ohta, S.; Tamari, M.; Hirota, T.; Yokoyama, T.; Niimi, A.; Mishima, M. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J. Allergy Clin. Immunol., 2013, 132, 305-312.
[125] O'Byrne, P. M.; Pedersen, S.; Lamm, C. J.; Tan, W. C.; Busse, W. W. Severe exacerbations and decline in lung function in asthma. Am. J. Respir. Crit. Care Med., 2009, 179, 19-24.
[126] de, Marco R.; Marcon, A.; Jarvis, D.; Accordini, S.; Bugiani, M.; Cazzoletti, L.; Cerveri, I.; Corsico, A.; Gislason, D.; Gulsvik, A.; Jogi, R.; Martinez-Moratalla, J.; Pin, I.; Janson, C. Inhaled steroids are associated with reduced lung function decline in subjects with asthma with elevated total IgE. J. Allergy Clin. Immunol., 2007, 119, 611-617.
[127] Bacci, E.; Cianchetti, S.; Bartoli, M.; Dente, F. L.; Di Franco, A.; Vagaggini, B.; Paggiaro, P. Low sputum eosinophils predict the lack of response to beclomethasone in symptomatic asthmatic patients. Chest, 2006, 129, 565-572.
[128] Cowan, D. C.; Cowan, J. O.; Palmay, R.; Williamson, A.; Taylor, D. R. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax, 2010, 65, 384-390.
[129] Michils, A.; Baldassarre, S.; Van Muylem, A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur. Respir. J., 2008, 31, 539-546.
[130] Little, S. A.; Chalmers, G. W.; MacLeod, K. J.; McSharry, C.; Thomson, N. C. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax, 2000, 55, 232-234.
[131] Pizzichini, M. M.; Pizzichini, E.; Clelland, L.; Efthimiadis, A.; Pavord, I.; Dolovich, J.; Hargreave, F. E. Prednisone-dependent asthma: inflammatory indices in induced sputum. Eur. Respir. J., 1999, 13, 15-21.
[132] Meijer, R. J.; Postma, D. S.; Kauffman, H. F.; Arends, L. R.; Koeter, G. H.; Kerstjens, H. A. Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma. Clin. Exp. Allergy, 2002, 32, 1096-1103.
[133] Castro, M.; Wenzel, S. E.; Bleecker, E. R.; Pizzichini, E.; Kuna, P.; Busse, W. W.; Gossage, D. L.; Ward, C. K.; Wu, Y.; Wang, B.; Khatry, D. B.; van der Merwe, R.; Kolbeck, R.; Molfino, N. A.; Raible, D. G. 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, 879-890.
[134] Castro, M.; Rubin, A. S.; Laviolette, M.; Fiterman, J.; De Andrade, Lima M.; Shah, P. L.; Fiss, E.; Olivenstein, R.; Thomson, N. C.; Niven, R. M.; Pavord, I. D.; Simoff, M.; Duhamel, D. R.; McEvoy, C.; Barbers, R.; Ten Hacken, N. H.; Wechsler, M. E.; Holmes, M.; Phillips, M. J.; Erzurum, S.; Lunn, W.; Israel, E.; Jarjour, N.; Kraft, M.; Shargill, N. S.; Quiring, J.; Berry, S. M.; Cox, G. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am. J. Respir. Crit. Care Med., 2010, 181, 116-124.
[135] Wechsler, M. E.; Laviolette, M.; Rubin, A. S.; Fiterman, J.; Lapa e Silva JR, Shah, P. L.; Fiss, E.; Olivenstein, R.; Thomson, N. C.; Niven, R. M.; Pavord, I. D.; Simoff, M.; Hales, J. B.; McEvoy, C.; Slebos, D. J.; Holmes, M.; Phillips, M. J.; Erzurum, S. C.; Hanania, N. A.; Sumino, K.; Kraft, M.; Cox, G.; Sterman, D. H.; Hogarth, K.; Kline, J. N.; Mansur, A. H.; Louie, B. E.; Leeds, W. M.; Barbers, R. G.; Austin, J. H.; Shargill, N. S.; Quiring, J.; Armstrong, B.; Castro, M. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J. Allergy Clin. Immunol., 2013, 132, 1295-1302