What have recent advances in therapy taught us about severe asthma disease mechanisms?

References

• 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.
   PubMed Web of Science ®Google Scholar
• Global Initiative for Asthma. GINA; 2019. [cited 2019 Apr 29]. Available from: http://ginasthma.org/
   Google Scholar
• Chen S, Golam S, Myers J, et al. Systematic literature review of the clinical, humanistic, and economic burden associated with asthma uncontrolled by GINA Steps 4 or 5 treatment. Curr Med Res Opin. 2018;34:2075–2088.
   Web of Science ®Google Scholar
• Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896.
   PubMed Web of Science ®Google Scholar
• Vianello A, Caminati M, Andretta M, et al. Prevalence of severe asthma according to the drug regulatory agency perspective: an Italian experience. World Allergy Organ J. 2019;12:100032. in press.
   Google Scholar
• O’Neill S, Sweeney J, Patterson CC, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British thoracic society difficult asthma registry. Thorax. 2015;70:376–378.
   PubMed Web of Science ®Google Scholar
• Chen S, Golam S, Myers J, et al. Systematic literature review of the clinical, humanistic, and economic burden associated with asthma uncontrolled by GINA Steps 4 or 5 treatment. Curr Med Res Opin. 2018;34(12):2075–2088.
   PubMed Web of Science ®Google Scholar
• Caminati M, Senna G. Uncontrolled severe asthma: starting from the unmet needs. Curr Med Res Opin. 2019;35(2):175–177.
   PubMed Web of Science ®Google Scholar
• Menzella F, Bertolini F, Biava M, et al. Severe refractory asthma: current treatment options and ongoing research. Drugs Context. 2018;7:212561.
   PubMedGoogle Scholar
• US FDA. Dupixent®(dupilumab) injection, for subcutaneous use: us prescribing information. [cited 2019 May 15]. Available from: https://www.Fda.Gov
   Google Scholar
• [cited 2019 May 15]. https://www.ema.europa.eu/en/medicines/human/EPAR/dupixent
   Google Scholar
• [cited 2019 May 15]. https://www.ema.europa.eu/en/news/new-add-treatment-patients-severe-asthma
   Google Scholar
• Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol. 2014;134(3):509–520.
   PubMed Web of Science ®Google Scholar
• Caminati M, Pham DL, Bagnasco D, et al. Type 2 immunity in asthma. World Allergy Organ J. 2018;11(1):13–23.
   PubMedGoogle Scholar
• Zhu TH, Zhu TR, Tran KA, et al. Epithelial barrier dysfunctions in atopic dermatitis: a skin-gut-lung model linking microbiome alteration and immune dysregulation. Br J Dermatol. 2018;179(3):570–581.
   PubMed Web of Science ®Google Scholar
• Loffredo LF, Abdala-Valencia H, Anekalla KR, et al. Beyond epithelial-to-mesenchymal transition: common suppression of differentiation programs underlies epithelial barrier dysfunction in mild, moderate, and severe asthma. Allergy. 2017;72:1988–2004.
   PubMed Web of Science ®Google Scholar
• Goleva E, Berdyshev E, Leung DY. Epithelial barrier repair and prevention of allergy. J Clin Invest. 2019;129(4):1463–1474.
   PubMed Web of Science ®Google Scholar
• Loxham M, Davies DE. Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients. J Allergy Clin Immunol. 2017;139(6):1736–1751.
   PubMed Web of Science ®Google Scholar
• Lloyd CM, Snelgrove RJ. Type 2 immunity: expanding our view. Sci Immunol. 2018 Jul 6;3(25):eaat1604.
   PubMed Web of Science ®Google Scholar
• Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest. 2019 Apr 1;129(4):1441–1451.
   PubMed Web of Science ®Google Scholar
• Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev. 2004;202:175–190.
   PubMed Web of Science ®Google Scholar
• Gurram RK, Zhu J. Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses. Cell Mol Immunol. 2019 Mar;16(3):225–235.
   PubMed Web of Science ®Google Scholar
• Liu S, Verma MM, Liu W, et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: the role of thymic stromal lymphopoietin. J Allergy Clin Immunol. 2018;141(1):257–268.e6.
   PubMed Web of Science ®Google Scholar
• Chen CC, Kobayashi T, Iijima K, et al. IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs. J Allergy Clin Immunol. 2017;140:1351–1363.e7.
   Web of Science ®Google Scholar
• Siracusa MC, Kim BS, Spergel JM, et al. Basophils and allergic inflammation. J Allergy Clin Immunol. 2013;132:789–801.
   PubMed Web of Science ®Google Scholar
• Egawa M, Mukai K, Yoshikawa S, et al. Inflammatory monocytes recruited to allergic skin acquire an anti-inflammatory M2 phenotype via basophil-derived interleukin-4. Immunity. 2013;38:570–580.
   PubMed Web of Science ®Google Scholar
• Thibodeaux Q, Smith MP, Ly K, et al. A review of dupilumab in the treatment of atopic diseases. Hum Vaccin Immunother. 2019;20:1–11.
   Google Scholar
• Edris A, De Feyter S, Maes T, et al. Monoclonal antibodies in type 2 asthma: a systematic review and network meta-analysis. Respir Res. 2019 Aug 8;20(1):179.
   PubMed Web of Science ®Google Scholar
• Allinne J, Scott G, Birchard D, et al. Broader impact of IL-4Rα blockade than IL-5 blockade on mediators of type 2 inflammation and lung pathology in a house dust mite-induced asthma mouse model. Am J Respir Crit Care Med. 2019;199:A5555.
   Web of Science ®Google Scholar
• Caminati M, Vianello A, Chieco Bianchi F, et al., NEONET Study Group. Relevance of Th2 markers in the assessment and therapeutic management of severe allergic asthma: a real life perspective. J Investig Allergol Clin Immunol. 2019 Jan 24;30:1–22.
   Google Scholar
• Ojanguren I, Chaboillez S, Lemiere C. Low blood eosinophil counts are not always a reliable marker of clinical response to mepolizumab in severe asthma. J Allergy Clin Immunol Pract. 2018;30:S2213–2198(18)30291–5.
   Google Scholar
• Silkoff PE, Laviolette M, Singh D, et al. Asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) longitudinal profiling study. Respir Res. 2015;16:142.
   PubMed Web of Science ®Google Scholar
• Malinovschi A, Fonseca JA, Jacinto T, et al. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132:821–827.
   Google Scholar
• Hastie AT, Moore WC, Li H, National Heart, Lung, and Blood Institute’s Severe Asthma Research Program, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132:72–80.
   PubMed Web of Science ®Google Scholar
• Crespo A, Giner J, Torrejón M, et al. Clinical and inflammatory features of asthma with dissociation between fractional exhaled nitric oxide and eosinophils in induced sputum. J Asthma. 2016;53:459–464.
   PubMed Web of Science ®Google Scholar
• Pelaia C, Vatrella A, Busceti MT, et al. Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab. Drug Des Devel Ther. 2017;11:3137–3144.
   PubMed Web of Science ®Google Scholar
• Bochner BS, Gleich GJ. What targeting eosinophils has taught us about their role in diseases. J Allergy Clin Immunol. 2010;126(1):16–25. quiz 26-7.
   PubMed Web of Science ®Google Scholar
• Stirling RG, van REL, Barnes PJ, et al. Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1403–1409.
   PubMed Web of Science ®Google Scholar
• 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(1):75–86 e8.
   PubMed Web of Science ®Google Scholar
• Ilmarinen P, Moilanen E, Kankaanranta H. Regulation of spontaneous eosinophil apoptosis-a neglected area of importance. J Cell Death. 2014;7:1–9.
   PubMedGoogle Scholar
• 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(2):248–255.
   PubMed Web of Science ®Google Scholar
• Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–1197.
   PubMed Web of Science ®Google Scholar
• Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198–1207.
   PubMed Web of Science ®Google Scholar
• 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(11):1062–1071.
   PubMed Web of Science ®Google Scholar
• Mepolizumab FDA Package insert. Secondary Mepolizumab FDA Package insert. [cited 2019 May 15]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf - 38 Drick
   Google Scholar
• Seeliger N, Welte B, Fuge T, et al. Anti-IL-5 therapy in patients with severe eosinophilic asthma - clinical efficacy and possible criteria for treatment response. BMC Pulm Med. 2018 Jul 18;18(1):119.
   PubMedGoogle Scholar
• Caminati M, Senna G. Biologic therapy in a patient with asthma and nasal polyps. J Allergy Clin Immunol Pract. 2019;7(5):1700–1701. May - Jun.
   PubMed Web of Science ®Google Scholar
• Mukherjee M, Nair P. Blood or sputum eosinophils to guide asthma therapy? Lancet Respir Med. 2015 Nov;3(11):824–825.
   PubMed Web of Science ®Google Scholar
• Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014 Dec;11(Suppl 5):S322–8.
   PubMedGoogle Scholar
• Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–366.
   PubMed Web of Science ®Google Scholar
• Corren J, Weinstein S, Janka L, et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016;150(4):799–810.
   PubMed Web of Science ®Google Scholar
• Weinstein SF, Katial RK, Bardin P, et al. Effects of reslizumab on asthma outcomes in a subgroup of eosinophilic asthma patients with self-reported chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2019;7(2):589–96 e3.
   PubMed Web of Science ®Google Scholar
• Reslizumab package insert. Secondary reslizumab package insert. [cited 2019 May 15]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761033lbl.pdf
   Google Scholar
• Lopez AF, Elliott MJ, Woodcock J, et al. IL-3 and IL-5: cross-competition on human haemopoietic cells. Immunol Today. 1992;13(12):495–500.
   PubMedGoogle Scholar
• Kolbeck R, Kozhich A, Koike M, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125(6):1344–53 e2.
   PubMed Web of Science ®Google Scholar
• 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(5):1086–96 e5.
   PubMed Web of Science ®Google Scholar
• Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–2127.
   PubMed Web of Science ®Google Scholar
• FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–2141.
   PubMed Web of Science ®Google Scholar
• Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017;376(25):2448–2458.
   PubMed Web of Science ®Google Scholar
• Busse WW, Bleecker ER, FitzGerald JM, et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir Med. 2019;7(1):46–59.
   PubMed Web of Science ®Google Scholar
• AstraZeneca. Fasenra package insert. secondary fasenra package insert. [cited 2019 May 15]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761070s000lbl.pdf
   Google Scholar
• Farne HA, Wilson A, Powell C, et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.
   PubMed Web of Science ®Google Scholar
• Bennich HH, Ishizaka K, Johansson SG, et al. a new class of human immunoglobulin. Immunology. 1968;15:323–324.
   PubMed Web of Science ®Google Scholar
• Finkelman FD, Urban JF Jr. The other side of the coin: the protective role of the Th2 cytokines. J Allergy Clin Immunol. 2001;107(5):772–780.
   PubMed Web of Science ®Google Scholar
• Ishizaka K, Ishizaka T, Hornbrook MM. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with gamma-E-globulin antibody. J Immunol. 1966;97:840–853.
   PubMed Web of Science ®Google Scholar
• Palomares O, Akdis M, Martín-Fontecha M, et al. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev. 2017;278:219–236.
   PubMed Web of Science ®Google Scholar
• Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15(1):57–65.
   PubMed Web of Science ®Google Scholar
• Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103(6):779–788.
   PubMed Web of Science ®Google Scholar
• Incorvaia C, Mauro M, Makri E, et al. Two decades with omalizumab: what we still have to learn. Biologics. 2018;12:135–142.
   PubMed Web of Science ®Google Scholar
• Schulman ES. Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders. Am J Respir Crit Care Med. 2001;164:S6–11.
   PubMed Web of Science ®Google Scholar
• Bonini M, Di Maria G, Paggiaro P, et al. Potential benefit of omalizumab in respiratory diseases. Ann Allergy Asthma Immunol. 2014;113(5):513–519.
   PubMed Web of Science ®Google Scholar
• Brożek JL, Bousquet J, Agache I, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines-2016 revision. J Allergy Clin Immunol. 2017;140(4):950–958.
   PubMed Web of Science ®Google Scholar
• 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(3):470–477.
   PubMedGoogle Scholar
• Moore WC, Bleecker ER, Curran-Everett D, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s severe asthma research program. J Allergy Clin Immunol. 2007;119(2):405–413.
   PubMed Web of Science ®Google Scholar
• Mouthuy J, Detry B, Sohy C, et al. Presence in sputum of functional dust mite-specific IgE antibodies in intrinsic asthma. Am J Respir Crit Care Med. 2011;184(2):206–214.
   PubMed Web of Science ®Google Scholar
• Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J. 2006;27(3):615–626.
   PubMed Web of Science ®Google Scholar
• Lombardi C, Savi E, Ridolo E, et al. Is allergic sensitization relevant in severe asthma? Which allergens may be culprit? World Allergy Organ J. 2017;10(1):2.
   PubMedGoogle Scholar
• Cardet JC, Casale TB. New insights into the utility of omalizumab. J Allergy Clin Immunol. 2019;143(3):923–926.
   PubMed Web of Science ®Google Scholar
• Froidure A, Shen C, Pilette C. Dendritic cells revisited in human allergic rhinitis and asthma. Allergy. 2016;71:137–148.
   PubMed Web of Science ®Google Scholar
• Schroeder JT, Bieneman AP, Chichester KL, et al. Decreases in human dendritic cell-dependent T(H)2-like responses after acute in vivo IgE neutralization. J Allergy Clin Immunol. 2010;125:896–901.
   PubMed Web of Science ®Google Scholar
• Dullaers M, Schuijs MJ, Willart M, et al. House dust mite-driven asthma and allergen-specific T cells depend on B cells when the amount of inhaled allergen is limiting. J Allergy Clin Immunol. 2017;140:76–88.
   PubMed Web of Science ®Google Scholar
• Matucci A, Vultaggio A, Maggi E, et al. Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question? Respir Res. 2018;19(1):113.
   PubMedGoogle Scholar
• Holt PG, Sly PD. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment. Nat Med. 2012;18:726–735.
   PubMed Web of Science ®Google Scholar
• Lynch P, Mazzone SB, Rogers MJ, et al. The plasmacytoid dendritic cell: at the cross-roads in asthma. Eur Respir J. 2014;43:264–275.
   PubMed Web of Science ®Google Scholar
• Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017;367:551–569.
   PubMed Web of Science ®Google Scholar
• Redhu NS, Gounni AS. The high affinity IgE receptor (FcεRI) expression and function in airway smooth muscle. Pulm Pharmacol Ther. 2013;26:86–94.
   PubMed Web of Science ®Google Scholar
• Roth M, Zhong J, Zumkeller C, et al. The role of IgE- receptors in IgE-dependent airway smooth muscle cell remodelling. PLoS One. 2013;8:e5601.
   Web of Science ®Google Scholar
• Mitchell PD, O’Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017;151:1338–1344.
   PubMed Web of Science ®Google Scholar
• Stokes JR, Casal TB. The use of Anti-IgE therapy beyond allergic asthma. J Allergy Clin Immunol Pract. 2015;3:162–166.
   PubMed Web of Science ®Google Scholar
• Pillai P, Chan YC, Wu SY, et al. Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J. 2016;48:1593–1601.
   PubMed Web of Science ®Google Scholar
• Hew M, Gillman A, Sutherland M, et al. Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria. Clin Exp Allergy. 2016 Nov;46(11):1407–1415.
   PubMed Web of Science ®Google Scholar
• Voskamp AL, Gillman A, Symons K. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2015;3(2):192–199. Mar-Apr. Epub 2015 Jan 29.
   PubMed Web of Science ®Google Scholar
• Arm JP, Bottoli I, Skerjanec A, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy. 2014 Nov;44(11):1371–1385.
   PubMed Web of Science ®Google Scholar
• Maggi L, Rossettini B, Montaini G, et al. Omalizumab dampens type 2 inflammation in a group of long-term treated asthma patients and detaches IgE from FcεRI. Eur J Immunol. 2018;48(12):2005–2014.
   PubMed Web of Science ®Google Scholar
• 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(2):184–190.
   PubMed Web of Science ®Google Scholar
• Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476–1485.
   PubMed Web of Science ®Google Scholar
• Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents. Pediatr Allergy Immunol. 2015;26(6):551–556.
   PubMed Web of Science ®Google Scholar
• 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(3):309–316.
   PubMed Web of Science ®Google Scholar
• Roth M, Zhao F, Zhong J, et al. Serum IgE induced airway smooth muscle cell remodeling is independent of allergens and is prevented by Omalizumab. PLoS One. 2015;10(9):e0136549.
   PubMed Web of Science ®Google Scholar
• 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(9):573–582.
   PubMed Web of Science ®Google Scholar
• Caminati M, Senna G, Guerriero M, et al. Omalizumab for severe allergic asthma in clinical trials and real-life studies: what we know and what we should address. Pulm Pharmacol Ther. 2015;31:28–35.
   PubMed Web of Science ®Google Scholar
• Tzortzaki EG, Georgiou A, Kampas D, et al. Long-term omalizumab treatment in severe allergic asthma: the south- eastern Mediterranean “real-life” experience. Pulm Pharmacol Ther. 2012;25:77e82.
   Web of Science ®Google Scholar
• Caminati M, Senna G, Chieco Bianchi F, et al. Omalizumab management beyond clinical trials: the added value of a network model. Pulm Pharmacol Ther. 2014 Oct;29(1):74–79.
   PubMed Web of Science ®Google Scholar
• Vennera M, Perez DC, De Llano L, et al. Omalizumab therapy in severe asthma: experience from the Spanish registryesome new approaches. J Asthma. 2012;49:416e22.
   Web of Science ®Google Scholar
• Verstraete K, Peelman F, Braun H, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun. 2017;8:14937.
   PubMed Web of Science ®Google Scholar
• Gauvreau GM, O’Byrne PM, Boulet LP, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370:2102–2110.
   PubMed Web of Science ®Google Scholar
• Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010 Sep 23;363(13):1211–1221.
   Web of Science ®Google Scholar
• Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936–946.
   PubMed Web of Science ®Google Scholar
• Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3:e3331.
   PubMed Web of Science ®Google Scholar
• Barlow JL, Peel S, Fox J, et al. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J Allergy Clin Immunol. 2013;132:933–941.
   PubMed Web of Science ®Google Scholar
• Mizutani N, Nabe T, Yoshino S. Interleukin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation of IgE-mediated airway inflammation and remodelling in mice. Immunology. 2013;139:205–218.
   PubMed Web of Science ®Google Scholar