Diagnosis and management of eosinophilic asthma: a US perspective

Hannah H Walford, Taylor A Doherty, Hannah H Walford, Taylor A Doherty

Abstract

Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma.

Keywords: IL-13; IL-4; Th2; allergy; asthma; eosinophil.

Figures

Figure 1
Figure 1
Schematic of eosinophils in airway inflammation and therapeutic targets. In response to allergens, viruses, or mucosal injury, airway epithelial cells produce cytokines, including IL-25, IL-33, and TSLP, which promote differentiation of Th2 cells, as well as activation of mast cells, macrophages, and type 2 innate lymphoid cells. IL-4 and IL-13 produced by Th2 and other cells results in eotaxin production, B-cell IgE class switching, airway hyperresponsiveness, and mucus secretion. IL-5 stimulates bone marrow eosinophil generation, and mediates recruitment, activation, and survival of eosinophils. GM-CSF produced by alveolar macrophages and eosinophils contributes to maturation and survival of eosinophils. Eosinophils release major basic protein, ROS, and enzymes, as well as Th2 cytokines and inflammatory lipid mediators including cysteinyl leukotrienes and prostaglandin D2. These products result in recruitment and activation of immune and structural cells. Further, production of Th2 cytokines and growth factors, such as TGF-β, contribute to features of airway remodeling in chronic asthma. A number of therapeutic targets (depicted by bullseyes) have been identified for eosinophilic asthma and are currently under investigation. Abbreviations: CRTH2, chemoattractant receptor homologous Th2; CystLTs, cysteinyl leukotrienes; GM-CSF, granulocyte macrophage-colony stimulating factor; IL, interleukin; ILC2, innate lymphoid cell type 2; IgE, immunoglobulin E; PGD2, prostaglandin D2; ROS, reactive oxygen species; Siglec-8, sialic acid binding Ig-like lectin 8; Th2, T-helper type 2; TGF-β, transforming growth factor beta; TSLP, thymic stromal lymphoprotein.

References

    1. Bateman ED, Boushey HA, Bousquet J, et al. GOAL Inverstigators Group Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med. 2004;170(8):836–844.
    1. Centers for Disease Control and Prevention Vital signs: asthma prevalence, disease characteristics, and self-management education: United States, 2001–2009. MMWR Morb Mortal Wkly Rep. 2011;60(17):547–552.
    1. Cisternas MG, Blanc PD, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol. 2003;111:1212–1218.
    1. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368:804–813.
    1. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–1119.
    1. Lotvall 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;127:355–360.
    1. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006;11:54–61.
    1. 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.
    1. Amelink M, de Groot JC, de Nijs SB, et al. Severe adult-onset asthma: a distinct phenotype. J Allergy Clin Immunol. 2013;132:336–341.
    1. Houston JC, De Navasquez S, Trounce JR. A clinical and pathological study of fatal cases of status asthmaticus. Thorax. 1953;8:207–213.
    1. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323:1033–1039.
    1. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med. 2000;161:64–72.
    1. Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005;115:720–727.
    1. Meijer RJ, Postma DS, Kauffman HF, Arends LR, Koeter GH, Kerstjens HA. Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma. Clin Exp Allergy. 2002;32:1096–1103.
    1. Berry M, Morgan A, Shaw DE, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007;62:1043–1049.
    1. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360:973–984.
    1. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985–993.
    1. Hamid Q, Tulic M. Immunobiology of asthma. Annu Rev Physiol. 2009;71:489–507.
    1. Barrett NA, Austen KF. Innate cells and T helper 2 cell immunity in airway inflammation. Immunity. 2009;31:425–437.
    1. Doherty T, Broide D. Cytokines and growth factors in airway remodeling in asthma. Curr Opin Immunol. 2007;19:676–680.
    1. Garty BZ, Kosman E, Ganor E, et al. Emergency room visits of asthmatic children, relation to air pollution, weather, and airborne allergens. Ann Allergy Asthma Immunol. 1998;81:563–570.
    1. D’Amato G, Cecchi L, Liccardi G. Thunderstorm-related asthma: not only grass pollen and spores. J Allergy Clin Immunol. 2008;121:537–538.
    1. Holgate ST. Innate and adaptive immune responses in asthma. Nat Med. 2012;18:673–683.
    1. Lee HC, Headley MB, Loo YM, et al. Thymic stromal lymphopoietin is induced by respiratory syncytial virus-infected airway epithelial cells and promotes a type 2 response to infection. J Allergy Clin Immunol. 2012;130:1187–1196. e5.
    1. Ziegler SF. Thymic stromal lymphopoietin and allergic disease. J Allergy Clin Immunol. 2012;130:845–852.
    1. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118:3546–3556.
    1. Wardlaw AJ, Brightling C, Green R, Woltmann G, Pavord I. Eosinophils in asthma and other allergic diseases. Br Med Bull. 2000;56:985–1003.
    1. Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med. 1995;182:1169–1174.
    1. Zietkowski Z, Tomasiak MM, Skiepko R, Bodzenta-Lukaszyk A. RANTES in exhaled breath condensate of stable and unstable asthma patients. Respir Med. 2008;102:1198–1202.
    1. Broide DH, Paine MM, Firestein GS. Eosinophils express interleukin 5 and granulocyte macrophage-colony-stimulating factor mRNA at sites of allergic inflammation in asthmatics. J Clin Invest. 1992;90:1414–1424.
    1. Broide DH, Firestein GS. Endobronchial allergen challenge in asthma. Demonstration of cellular source of granulocyte macrophage colony-stimulating factor by in situ hybridization. J Clin Invest. 1991;88:1048–1053.
    1. Davies D, Larbi K, Allen A, et al. VCAM-1 contributes to rapid eosinophil accumulation induced by the chemoattractants PAF and LTB4: evidence for basal expression of functional VCAM-1 in rat skin. Immunology. 1999;97:150–158.
    1. Stirling RG, van Rensen EL, Barnes PJ, Chung KF. Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am J Respir Crit Care Med. 2001;164:1403–1409.
    1. Cho JY, Miller M, Baek KJ, et al. Inhibition of airway remodeling in IL-5-deficient mice. J Clin Invest. 2004;113:551–560.
    1. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–259.
    1. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360:1715–1721.
    1. Woodruff PG, Khashayar R, Lazarus SC, et al. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma. J Allergy Clin Immunol. 2001;108:753–758.
    1. Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med. 2000;161:9–16.
    1. Porsbjerg C, Lund TK, Pedersen L, Backer V. Inflammatory subtypes in asthma are related to airway hyperresponsiveness to mannitol and exhaled NO. J Asthma. 2009;46:606–612.
    1. Crimi E, Spanevello A, Neri M, Ind PW, Rossi GA, Brusasco V. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am J Respir Crit Care Med. 1998;157:4–9.
    1. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113:101–108.
    1. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med. 2004;170:601–605.
    1. Thomson NC, Chaudhuri R. Why is eosinophilic bronchitis not asthma? Am J Respir Crit Care Med. 2004;170:4–5.
    1. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002;346:1699–1705.
    1. Kanazawa H, Nomura S, Yoshikawa J. Role of microvascular permeability on physiologic differences in asthma and eosinophilic bronchitis. Am J Respir Crit Care Med. 2004;169:1125–1130.
    1. Frick WE, Sedgwick JB, Busse WW. The appearance of hypodense eosinophils in antigen-dependent late phase asthma. Am Rev Respir Dis. 1989;139:1401–1406.
    1. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy. 1995;25:820–827.
    1. Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132:72–80.
    1. D’Silva L, Cook RJ, Allen CJ, Hargreave FE, Parameswaran K. Changing pattern of sputum cell counts during successive exacerbations of airway disease. Respir Med. 2007;101:2217–2220.
    1. Good JT, Jr, Kolakowski CA, Groshong SD, Murphy JR, Martin RJ. Refractory asthma: importance of bronchoscopy to identify phenotypes and direct therapy. Chest. 2011;141:599–606.
    1. Silkoff PE, Lent AM, Busacker AA, et al. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. J Allergy Clin Immunol. 2005;116:1249–1255.
    1. Mahr TA, Malka J, Spahn JD. Inflammometry in pediatric asthma: a review of fractional exhaled nitric oxide in clinical practice. Allergy Asthma Proc. 2013;34:210–219.
    1. Barnes PJ, Dweik RA, Gelb AF, et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest. 2010;138:682–692.
    1. 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;352:2163–2173.
    1. Tseliou E, Bessa V, Hillas G, et al. Exhaled nitric oxide and exhaled breath condensate pH in severe refractory asthma. Chest. 2010;138:107–113.
    1. Blanchard C, Mingler MK, McBride M, et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008;1:289–296.
    1. Ouyang G, Liu M, Ruan K, Song G, Mao Y, Bao S. Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett. 2009;281:213–219.
    1. 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. e10.
    1. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–1098.
    1. Masuoka M, Shiraishi H, Ohta S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122:2590–2600.
    1. Gordon ED, Sidhu SS, Wang ZE, et al. A protective role for periostin and TGF-beta in IgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy. 2012;42:144–155.
    1. Kulkarni NS, Hollins F, Sutcliffe A, et al. Eosinophil protein in airway macrophages: a novel biomarker of eosinophilic inflammation in patients with asthma. J Allergy Clin Immunol. 2010;126:61–69. e3.
    1. Barnes PJ. Severe asthma: advances in current management and future therapy. J Allergy Clin Immunol. 2012;129:48–59.
    1. Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol. 2002;109:649–657.
    1. Maneechotesuwan K, Xin Y, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol. 2007;178:2491–2498.
    1. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358–1375.
    1. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373:1905–1917.
    1. Mizue Y, Ghani S, Leng L, et al. Role for macrophage migration inhibitory factor in asthma. Proc Natl Acad Sci U S A. 2005;102:14410–14415.
    1. Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov. 2012;11:958–972.
    1. Saini SS, MacGlashan DW, Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE-infusions is reversible in vitro and in vivo. J Immunol. 1999;162:5624–5630.
    1. 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;60:309–316.
    1. Ayres JG, Higgins B, Chilvers ER, Ayre G, Blogg M, Fox H. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma. Allergy. 2004;59:701–708.
    1. Vignola AM, Humbert M, Bousquet J, et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR. Allergy. 2004;59:709–717.
    1. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:184–190.
    1. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18:254–261.
    1. Lanier BQ, Corren J, Lumry W, Liu J, Fowler-Taylor A, Gupta N. Omalizumab is effective in the long-term control of severe allergic asthma. Ann Allergy Asthma Immunol. 2003;91:154–159.
    1. Holgate ST, Chuchalin AG, Hebert J, et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy. 2004;34:632–638.
    1. Bousquet J, Rabe K, Humbert M, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med. 2007;101:1483–1492.
    1. Noga O, Hanf G, Brachmann I, et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol. 2006;117:1493–1499.
    1. Djukanovic R, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170:583–593.
    1. Noga O, Hanf G, Kunkel G. Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. Int Arch Allergy Immunol. 2003;131:46–52.
    1. Milgrom H, Fick RB, Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med. 1999;341:1966–1973.
    1. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115:459–465.
    1. Chand HS, Schuyler M, Joste N, et al. Anti-IgE therapy results in decreased myeloid dendritic cells in asthmatic airways. J Allergy Clin Immunol. 2010;125:1157–1158. e5.
    1. Kaya H, Gumus S, Ucar E, et al. Omalizumab as a steroid-sparing agent in chronic eosinophilic pneumonia. Chest. 2012;142:513–516.
    1. Hamid Q, Azzawi M, Ying S, et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest. 1991;87:1541–1546.
    1. Humbert M, Corrigan CJ, Kimmitt P, Till SJ, Kay AB, Durham SR. Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med. 1997;156:704–708.
    1. Garlisi CG, Kung TT, Wang P, et al. Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation. Am J Respir Cell Mol Biol. 1999;20:248–255.
    1. Gnanakumaran G, Babu KS. Technology evaluation: mepolizumab, GlaxoSmithKline. Curr Opin Mol Ther. 2003;5:321–325.
    1. Menzies-Gow A, Flood-Page P, Sehmi R, et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol. 2003;111:714–719.
    1. Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med. 2003;167:1655–1659.
    1. 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;356:2144–2148.
    1. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176:1062–1071.
    1. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184:1125–1132.
    1. Busse WW, Katial R, Gossage D, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125:1237–1244. e2.
    1. Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086–1096. e5.
    1. Ingram JL, Kraft M. IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. J Allergy Clin Immunol. 2012;130:829–842.
    1. Hart TK, Blackburn MN, Brigham-Burke M, et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130:93–100.
    1. Henderson WR, Jr, Chi EY, Maliszewski CR. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J Immunol. 2000;164:1086–1095.
    1. Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol. 2001;107:963–970.
    1. Wenzel S, Wilbraham D, Fuller R, Getz EB, 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.
    1. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455–2466.
    1. Pope SM, Brandt EB, Mishra A, et al. IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001;108:594–601.
    1. Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY. A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol. 1996;157:2654–2659.
    1. Yang G, Volk A, Petley T, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine. 2004;28:224–232.
    1. Bree A, Schlerman FJ, Wadanoli M, et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J Allergy Clin Immunol. 2007;119:1251–1257.
    1. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med. 2011;183:1007–1014.
    1. Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330–338.
    1. Tamachi T, Maezawa Y, Ikeda K, et al. IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice. J Allergy Clin Immunol. 2006;118:606–614.
    1. Fujita J, Kawaguchi M, Kokubu F, et al. Interleukin-33 induces interleukin-17F in bronchial epithelial cells. Allergy. 2012;67:744–750.
    1. Shi L, Leu SW, Xu F, et al. Local blockade of TSLP receptor alleviated allergic disease by regulating airway dendritic cells. Clin Immunol. 2008;129:202–210.
    1. Amgen Double-blind, Multiple Dose Study in Subjects With Mild Atopic Asthma. [Accessed February 3, 2014]. Available from: . NLM identifier: NCT01405963.
    1. Gauvreau GM, Boulet LP, Cockcroft DW, et al. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. Am J Respir Crit Care Med. 2008;177:952–958.
    1. Krinner EM, Raum T, Petsch S, et al. A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. Mol Immunol. 2007;44:916–925.
    1. Kiwamoto T, Kawasaki N, Paulson JC, Bochner BS. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol Ther. 2012;135:327–336.
    1. Wenzel SE, Barnes PJ, Bleecker ER, et al. 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.
    1. Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J. 2011;37:1352–1359.
    1. Castro M, Musani AI, Mayse ML, Shargill NS. Bronchial thermoplasty: a novel technique in the treatment of severe asthma. Ther Adv Respir Dis. 2010;4:101–116.
    1. Castro M, Rubin AS, Laviolette M, et al. 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. 2012;181:116–124.
    1. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med. 2011;11:8.

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