Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.

7th Respiratory Medicine Department and Asthma Centre Athens Chest Hospital Athens Greece

Allergy and Clinical Immunology Research Group Department of Microbiology Immunology and Transplantation KU Leuven Leuven Belgium

Allergy Center Ruhr University Bochum Bochum Germany

Centre for Experimental Medicine School of Medicine Dentistry and Biomedical Sciences Queen's University Belfast Belfast UK

Children's Center Protestant Hospital Bethel Bielefeld Germany

Department of Allergy and Clinical Immunology Faculty of Medicine Transylvania University Brasov Brasov Romania

Department of Biomedical Sciences Humanitas University Milan Italy

Department of Clinical Pharmacy and Pharmacology UMCG and QPS NL Groningen The Netherlands

Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Department of Pediatrics Division of Pediatric Allergy and Asthma Gazi University School of Medicine Ankara Turkey

Department of Respiratory Medicine 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Respiratory Medicine Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

Department of Respiratory Medicine and Allergology Institute for Clinical Science Skane University Hospital Lund Sweden

Department of Women's and Children's Health Uppsala University Uppsala Sweden

Division of Infection Immunity and Respiratory Medicine Faculty of Biology Medicine and Health Manchester Academic Health Sciences Centre University of Manchester and University Hospital of South Manchester NHS Foundation Trust Manchester UK

Division of Pediatric Allergy Faculty of Medicine Hacettepe University Ankara Turkey

Experimental Asthma and Allergy Research Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Technology University of Tartu Tartu Estonia

Personalized Medicine Asthma and Allergy Humanitas Research Hospital Milan Italy

Respiratory Medicine Department University of Ioannina Medical School Ioannina Greece

Section of Allergology Department of Internal Medicine Erasmus Medical Center Rotterdam the Netherlands

Section of Occupational and Environmental Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Section of Paediatrics Department of Medicine Imperial College London London UK

Zobrazit více v PubMed

Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45-56.

Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391(10122):783-800.

Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57(10):875-879.

Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2009;181(4):315-323.

Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218-224.

Fahy JV. Type 2 inflammation in asthma-present in most, absent in many. Nat Rev Immunol. 2015;15(1):57-65.

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(2):343-373.

Wu W, Bleecker E, Moore W, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol. 2014;133(5):1280-1288.

Kuo C-HS, Pavlidis S, Loza M, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017;49(2).

Seys SF, Scheers H, Van den Brande P, et al. Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir Res. 2017;18(1):39.

Richards LB, Neerincx AH, van Bragt JJMH, Sterk PJ, Bel EHD, Maitland-van der Zee AH. Biomarkers and asthma management: analysis and potential applications. Curr Opin Allergy Clin Immunol. 2018;18(2):96-108.

Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835-846.

Muraro A, Lemanske RF, Hellings PW, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-1358.

Hollander Z, DeMarco ML, Sadatsafavi M, McManus BM, Ng RT, Sin DD. Biomarker development in COPD: moving from P values to products to impact patient care. Chest. 2017;151(2):455-467.

FDA CDER Biomarker Qualification Program [Internet]. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm. Accessed October 1, 2018.

Hekking P-P, Loza MJ, Pavlidis S, et al. Transcriptomic gene signatures associated with persistent airflow limitation in patients with severe asthma. Eur Respir J. 2017;50(3).

Hekking P-P, Loza MJ, Pavlidis S, et al. Pathway discovery using transcriptomic profiles in adult-onset severe asthma. J Allergy Clin Immunol 2018;141(4):1280-1290.

Alexis NE. Biomarker sampling of the airways in asthma. Curr Opin Pulm Med. 2014;20(1):46-52.

Seys SF. Role of sputum biomarkers in the management of asthma. Curr Opin Pulm Med. 2017;23(1):34-40.

Zuiker RGJA, Tribouley C, Diamant Z, et al. Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test. Eur Clin Respir J. 2016;3:31324.

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(2):115-120.

Fowler SJ, Tavernier G, Niven R. High blood eosinophil counts predict sputum eosinophilia in patients with severe asthma. J Allergy Clin Immunol. 2015;135(3):822-824.

Agache I, Strasser DS, Klenk A, et al. Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics. Allergy. 2016;71(8):1192-1202.

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(4):290-300.

Ullmann N, Bossley CJ, Fleming L, Silvestri M, Bush A, Saglani S. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy. 2013;68(3):402-406.

Spector SL, Tan RA. Is a single blood eosinophil count a reliable marker for “eosinophilic asthma?”. J Asthma. 2012;49(8):807-810.

Ludviksdottir D, Diamant Z, Alving K, Bjermer L, Malinovschi A. Clinical aspects of using exhaled NO in asthma diagnosis and management. Clin Respir J. 2012;6(4):193-207.

Neerincx AH, Vijverberg SJH, Bos LDJ, et al. Breathomics from exhaled volatile organic compounds in pediatric asthma. Pediatr Pulmonol. 2017;52(12):1616-1627.

Boot JD, de Kam ML, Mascelli MA, et al. Nasal nitric oxide: longitudinal reproducibility and the effects of a nasal allergen challenge in patients with allergic rhinitis. Allergy. 2007;62(4):378-384.

Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010;181(10):1033-1041.

Bos LD, Sterk PJ, Fowler SJ. Breathomics in the setting of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(4):970-976.

Almstrand A-C, Ljungström E, Lausmaa J, Bake B, Sjövall P, Olin A-C. Airway monitoring by collection and mass spectrometric analysis of exhaled particles. Anal Chem. 2009;81(2):662-668.

Larsson P, Lärstad M, Bake B, et al. Exhaled particles as markers of small airway inflammation in subjects with asthma. Clin Physiol Funct Imaging. 2017;37(5):489-497.

Farzan N, Vijverberg SJ, Kabesch M, Sterk PJ, Maitland-van der Zee AH. The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: where do we stand? Pediatr Pulmonol. 2018;53(6):836-845.

Huang YJ, Boushey HA. The microbiome in asthma. J Allergy Clin Immunol. 2015;135(1):25-30.

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(1):1-10.

Seys SF, Grabowski M, Adriaensen W, et al. Sputum cytokine mapping reveals an “IL-5, IL-17A, IL-25-high” pattern associated with poorly controlled asthma. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2013;43(9):1009-1017.

Peters MC, Mekonnen ZK, Yuan S, Bhakta NR, Woodruff PG, Fahy JV. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388-394.

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(5):388-395.

Bhakta NR, Solberg OD, Nguyen CP, et al. A qPCR-based metric of Th2 airway inflammation in asthma. Clin Transl Allergy. 2013;3(1):24.

Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med. 2013;19(8):977-979.

Soma T, Iemura H, Naito E, et al. Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma. Allergol Int. 2018;67:S3-S11.

Kortekaas Krohn I, Shikhagaie MM, Golebski K, et al. Emerging roles of innate lymphoid cells in inflammatory diseases: clinical implications. Allergy. 2018;73(4):837-850.

Zissler UM, Esser-von Bieren J, Jakwerth CA, Chaker AM, Schmidt-Weber CB. Current and future biomarkers in allergic asthma. Allergy. 2016;71(4):475-494.

Berry M, Morgan A, Shaw DE, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007;62(12):1043-1049.

Gibson PG. Inflammatory phenotypes in adult asthma: clinical applications. Clin Respir J. 2009;3(4):198-206.

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(3):199-208.

2018 GINA Report, Global Strategy for Asthma Management and Prevention [Internet]. 2018. www.ginasthma.org. Accessed October 1, 2018.

Schleich FN, Chevremont A, Paulus V, et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J. 2014;44(1):97-108.

Kostikas K, Zervas E, Gaga M. Airway and systemic eosinophilia in asthma: does site matter? Eur Respir J. 2014;44(1):14-16.

Mukherjee M, Nair P. Blood or sputum eosinophils to guide asthma therapy? Lancet Respir Med. 2015;3(11):824-825.

Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016;138(6):1608-1618.

Wolfe MG, Mukherjee M, Radford K, Brennan JD, Nair P. Rapid quantification of sputum eosinophil peroxidase on a lateral flow test strip. Allergy. 2018. https://doi.org/10.1111/all.13711

Choy DF, Hart KM, Borthwick LA, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7(301):301ra129.

Brown KR, Krouse RZ, Calatroni A, et al. Endotypes of difficult-to-control asthma in inner-city African American children. PLoS One 2017;12(7):e0180778.

Agache I, Strasser DS, Pierlot GM, Farine H, Izuhara K, Akdis CA. Monitoring inflammatory heterogeneity with multiple biomarkers for multidimensional endotyping of asthma. J Allergy Clin Immunol. 2018;141(1):442-445.

Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602-615.

Bjermer L, Alving K, Diamant Z, et al. Current evidence and future research needs for FeNO measurement in respiratory diseases. Respir Med. 2014;108(6):830-841.

Kostikas K, Minas M, Papaioannou AI, Papiris S, Dweik RA. Exhaled nitric oxide in asthma in adults: the end is the beginning? Curr Med Chem. 2011;18(10):1423-1431.

Zuiker RGJA, Boot JD, Calderon C, et al. Sputum induction with hypertonic saline reduces fractional exhaled nitric oxide in chronic smokers and non-smokers. Respir Med. 2010;104(6):917-920.

Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. 2018;73(12):1110-1119.

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.

de Vries R, Dagelet YWF, Spoor P, et al. Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label. Eur Respir J. 2018;51(1).

Fens N, van der Sluijs KF, van de Pol MA, et al. Electronic nose identifies bronchoalveolar lavage fluid eosinophils in asthma. Am J Respir Crit Care Med. 2015;191(9):1086-1088.

Brinkman P, van de Pol MA, Gerritsen MG, et al. Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2017;47(9):1159-1169.

van der Schee MP, Palmay R, Cowan JO, Taylor DR. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2013;43(11):1217-1225.

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(3):647-654.

Simpson JL, Yang IA, Upham JW, et al. Periostin levels and eosinophilic inflammation in poorly-controlled asthma. BMC Pulm Med. 2016;16(1):67.

Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088-1098.

Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748-756.

James A, Hedlin G. Biomarkers for the phenotyping and monitoring of asthma in children. Curr Treat Options Allergy. 2016;3(4):439-452.

Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692-701.

Diamant Z, Timmers MC, van der Veen H, et al. The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo. J Allergy Clin Immunol. 1995;95(1 Pt 1):42-51.

Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-exacerbated respiratory disease (N-ERD)-a EAACI position paper. Allergy. 2019;74(1):28-39.

Hagan JB, Laidlaw TM, Divekar R, et al. Urinary leukotriene E4 to determine aspirin intolerance in asthma: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2017;5(4):990-997.

Demarche S, Schleich F, Henket M, Paulus V, Van Hees T, Louis R. Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory? BMC Pulm Med. 2016;16:46.

Hilvering B, Vijverberg SJH, Jansen J, et al. Diagnosing eosinophilic asthma using a multivariate prediction model based on blood granulocyte responsiveness. Allergy. 2017;72(8):1202-1211.

Pettipher R, Hunter MG, Perkins CM, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223-1232.

Hanratty CE, Matthews JG, Arron JR, et al. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials. 2018;19(1):5.

Nagasaki T, Matsumoto H, Kanemitsu Y, et al. Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma. Am J Respir Crit Care Med. 2014;190(12):1449-1452.

Schleich FN, 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.

Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirol Carlton Vic. 2006;11(1):54-61.

Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557-1563.

Telenga ED, Kerstjens HAM, Ten Hacken NHT, Postma DS, van den Berge M. Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics. BMC Pulm Med. 2013;13:58.

Telenga ED, Tideman SW, Kerstjens HAM, et al. Obesity in asthma: more neutrophilic inflammation as a possible explanation for a reduced treatment response. Allergy. 2012;67(8):1060-1068.

Marijsse GS, Seys SF, Schelpe A-S, et al. Obese individuals with asthma preferentially have a high IL-5/IL-17A/IL-25 sputum inflammatory pattern. Am J Respir Crit Care Med. 2014;189(10):1284-1285.

Alam R, Good J, Rollins D, et al. Airway and serum biochemical correlates of refractory neutrophilic asthma. J Allergy Clin Immunol. 2017;140(4):1004-1014.

Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med. 2008;177(2):148-155.

Wang F, He XY, Baines KJ, et al. Different inflammatory phenotypes in adults and children with acute asthma. Eur Respir J. 2011;38(3):567-574.

Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129(4):974-982.

Andersson CK, Adams A, Nagakumar P, et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J Allergy Clin Immunol. 2017;139(6):1819-1829.

Su M-W, Lin W-C, Tsai C-H, et al. Childhood asthma clusters reveal neutrophil-predominant phenotype with distinct gene expression. Allergy. 2018;73(10):2024-2032.

Jones CE, Chan K. Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha, and granulocyte-colony-stimulating factor by human airway epithelial cells. Am J Respir Cell Mol Biol. 2002;26(6):748-753.

Bullens DMA, Decraene A, Seys S, Dupont LJ. IL-17A in human respiratory diseases: innate or adaptive immunity? Clinical implications Clin Dev Immunol 2013;2013:840315.

Baines KJ, Simpson JL, Wood LG, et al. Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. J Allergy Clin Immunol. 2014;133(4):997-1007.

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(4):1067-1076.

Rossios C, Pavlidis S, Hoda U, et al. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J Allergy Clin Immunol. 2018;141(2):560-570.

Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor α in refractory asthma. N Engl J Med. 2006;354(7):697-708.

Manni ML, Trudeau JB, Scheller EV, et al. The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol. 2014;7(5):1186-1198.

Agache I, Ciobanu C, Agache C, Anghel M. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med. 2010;104(8):1131-1137.

Silvestri M, Bontempelli M, Giacomelli M, et al. High serum levels of tumour necrosis factor-α and interleukin-8 in severe asthma: markers of systemic inflammation? Clin Exp Allergy. 2006;36(11):1373-1381.

Decaesteker T, Seys S, Hox V, et al. Serum and sputum calprotectin, a reflection of neutrophilic airway inflammation in asthmatics after high-altitude exposure. Clin Exp Allergy. 2017;47(12):1675-1677.

Horváth I, Hunt J, Barnes PJ, et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J. 2005;26(3):523-548.

Ntontsi P, Loukides S, Bakakos P, et al. Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: comparison with different sputum phenotypes. Allergy. 2017;72(11):1761-1767.

Fixman ED, Stewart A, Martin JG. Basic mechanisms of development of airway structural changes in asthma. Eur Respir J. 2007;29(2):379-389.

James AL, Elliot JG, Jones RL, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185(10):1058-1064.

Ordoñez C, Ferrando R, Hyde DM, Wong HH, Fahy JV. Epithelial desquamation in asthma: artifact or pathology? Am J Respir Crit Care Med. 2000;162(6):2324-2329.

Payne DNR, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167(1):78-82.

Barbato A, Turato G, Baraldo S, et al. Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med. 2006;174(9):975-981.

Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet Lond Engl. 1989;1(8637):520-524.

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(10):1360-1368.

Sumi Y, Hamid Q. Airway remodeling in asthma. Allergol Int. 2007;56(4):341-348.

Ward C, Pais M, Bish R, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax. 2002;57(4):309-316.

Sont JK, Willems LN, Bel EH, van KJ, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med. 1999;1:1043-1051.

Flood-Page P, Menzies-Gow A, Phipps S, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003;112(7):1029-1036.

Nuijsink M, Hop WCJ, Sterk PJ, Duiverman EJ, de Jongste JC. Long-term asthma treatment guided by airway hyperresponsiveness in children: a randomised controlled trial. Eur Respir J. 2007;30(3):457-466.

Booms P, Cheung D, Timmers MC, Zwinderman AH, Sterk PJ. Protective effect of inhaled budesonide against unlimited airway narrowing to methacholine in atopic patients with asthma. J Allergy Clin Immunol. 1997 Mar;99(3):330-337.

Ulrik CS, Diamant Z. Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2010;40(4):576-581.

Riccio AM, Mauri P, De Ferrari L, et al. Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months. Clin Transl Allergy. 2017;7:6.

Mauri P, Riccio AM, Rossi R, et al. Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett. 2014;162(1 Pt A):2-10.

Cortegano I, del PV, Cárdaba B, et al. Galectin-3 down-regulates IL-5 gene expression on different cell types. J Immunol Baltim Md 1950. 1998;161(1):385-389.

Lee CG, Da Silva CA, Dela Cruz CS, et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol. 2011;73:479-501.

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(2):328-335.

Yick CY, Zwinderman AH, Kunst PW, et al. Gene expression profiling of laser microdissected airway smooth muscle tissue in asthma and atopy. Allergy. 2014;69(9):1233-1240.

Yick CY, Zwinderman AH, Kunst PW, et al. Glucocorticoid-induced changes in gene expression of airway smooth muscle in patients with asthma. Am J Respir Crit Care Med. 2013;187(10):1076-1084.

Ammit AJ, Burgess JK, Hirst SJ, et al. The effect of asthma therapeutics on signalling and transcriptional regulation of airway smooth muscle function. Pulm Pharmacol Ther. 2009;22(5):446-454.

Slats AM, Sont JK, van Klink RHCJ, Bel EHD, Sterk PJ. Improvement in bronchodilation following deep inspiration after a course of high-dose oral prednisone in asthma. Chest. 2006;130(1):58-65.

Tufvesson E, Aronsson D, Bjermer L. Cysteinyl-leukotriene levels in sputum differentiate asthma from rhinitis patients with or without bronchial hyperresponsiveness. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2007;37(7):1067-1073.

de Kluijver J, Schrumpf JA, Evertse CE, et al. Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2005;35(10):1361-1369.

Niimi A, Matsumoto H, Amitani R, et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med. 2004;116(11):725-731.

Hoshino M, Ohtawa J, Akitsu K. Association of airway wall thickness with serum periostin in steroid-naive asthma. Allergy Asthma Proc. 2016;37(3):225-230.

Ebenezer JA, Christensen JM, Oliver BG, et al. Periostin as a marker of mucosal remodelling in chronic rhinosinusitis. Rhinology. 2017;55(3):234-241.

Yick CY, von der Thüsen JH, Bel EH, Sterk PJ, Kunst PW. In vivo imaging of the airway wall in asthma: fibered confocal fluorescence microscopy in relation to histology and lung function. Respir Res. 2011;2(1):85.

Wijmans L, d'Hooghe JNS, Bonta PI, Annema JT. Optical coherence tomography and confocal laser endomicroscopy in pulmonary diseases. Curr Opin Pulm Med. 2017;23(3):275-283.

Boyman O, Kaegi C, Akdis M, et al. EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders. Allergy. 2015;70(7):727-754.

Shamji MH, Kappen JH, Akdis M, et al. Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper. Allergy. 2017;72(8):1156-1173.

Busse WW. Anti-immunoglobulin E (omalizumab) therapy in allergic asthma. Am J Respir Crit Care Med. 2001;164(8 Pt 2):S12-S17.

Thomson NC, Chaudhuri R. Omalizumab: clinical use for the management of asthma. Clin Med Insights Circ Respir Pulm Med. 2012;6:27-40.

Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;(1):CD003559.

Casale TB, Luskin AT, Busse W, et al. Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, a prospective real-world study. J Allergy Clin Immunol Pract. 2019;7(1):156-164.

Pike KC, Akhbari M, Kneale D, Harris KM. Interventions for autumn exacerbations of asthma in children. Cochrane Database Syst Rev. 2018;3:CD012393.

Wahn U, Martin C, Freeman P, Blogg M, Jimenez P. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy. 2009;64(12):1780-1787.

Korn S, Haasler I, Fliedner F, et al. Monitoring free serum IgE in severe asthma patients treated with omalizumab. Respir Med. 2012;106(11):1494-1500.

Humbert M, Busse W, Hanania NA, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2(5):525-536.

Johansson SGO, Lilja G, Hallberg J, Nopp A. A clinical follow-up of omalizumab in routine treatment of allergic asthma monitored by CD-sens. Immun Inflamm Dis. 2018;6(3):382-391.

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(8):804-811.

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.

Fleming L, Koo M, Bossley CJ, Nagakumar P, Bush A, Saglani S. The utility of a multidomain assessment of steroid response for predicting clinical response to omalizumab. J Allergy Clin Immunol. 2016;138(1):292-294.

Nair P. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985-993.

Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973-984.

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):1086-1096.

Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9:CD010834.

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.

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.

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.

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.

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.

Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet Lond Engl. 2012;380(9842):651-659.

Slager RE, Otulana BA, Hawkins GA, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J Allergy Clin Immunol. 2012;130(2):516-522.

Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486-2496.

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.

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.

Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016;315(5):469-479.

Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475-2485.

Woodruff PG, Boushey HA, Dolganov GM, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA. 2007;104(40):15858-15863.

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.

Kanemitsu Y, Matsumoto H, Izuhara K, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132(2):305-312.

Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H, Ziegler SF. The multiple facets of thymic stromal lymphopoietin (TSLP) during allergic inflammation and beyond. J Leukoc Biol. 2012;91(6):877-886.

Ito T, Liu Y-J, Arima K. Cellular and molecular mechanisms of TSLP function in human allergic disorders-TSLP programs the “Th2 code” in dendritic cells. Allergol Int. 2012;61(1):35-43.

Ying S, O'Connor B, Ratoff J, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol Baltim Md 1950. 2005;174(12):8183-8190.

Gauvreau GM, O'Byrne PM, Boulet L-P, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014;370(22):2102-2110.

Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936-946.

Hirai H, Tanaka K, Yoshie O, et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001;193(2):255-261.

Xue L, Salimi M, Panse I, et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol. 2014;133(4):1184-1194.

Singh D, Cadden P, Hunter M, et al. Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J. 2013;41(1):46-52.

Diamant Z, Sidharta PN, Singh D, et al. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014;44(8):1044-1052.

Fajt ML, Gelhaus SL, Freeman B, et al. Prostaglandin D₂ pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol. 2013;131(6):1504-1512.

Kuna P, Bjermer L, Tornling G. Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma. Drug Des Devel Ther. 2016;10:2759-2770.

Hall IP, Fowler AV, Gupta A, et al. Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther. 2015;32:37-44.

Bateman ED, Guerreros AG, Brockhaus F, et al. Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur Respir J. 2017;50(2).

Gonem S, Berair R, Singapuri A, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4(9):699-707.

Diamant Z, Aalders W, Parulekar A, Bjermer L, Hanania NA. Targeting lipid mediators in asthma: time for reappraisal. Curr Opin Pulm Med. 2019;25(1):121-127.

Anticevich SZ, Hughes JM, Black JL, Armour CL. Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha. Eur J Pharmacol. 1995;284(1-2):221-225.

Howarth PH, Babu KS, Arshad HS, et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax. 2005;60:1012-1018.

Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor- blockade in severe persistent asthma. Am J Respir Crit Care Med. 2009;179(7):549-558.

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.

Gernez Y, Tirouvanziam R, Chanez P. Neutrophils in chronic inflammatory airway diseases: can we target them and how? Eur Respir J. 2010;35(3):467-469.

Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42(7):1097-1103.

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.

Shinkai M, Henke MO, Rubin BK. Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action. Pharmacol Ther. 2008;117(3):393-405.

Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-329.

Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2017;390(10095):659-668.

Trivedi A, Pavord ID, Castro M. Bronchial thermoplasty and biological therapy as targeted treatments for severe uncontrolled asthma. Lancet Respir Med. 2016;4(7):585-592.

Facciolongo N, Di Stefano A, Pietrini V, et al. Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma. BMC Pulm Med. 2018;18(1):29.

Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356(13):1327-1337.

Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176(12):1185-1191.

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. 2010;181(2):116-124.

Chupp G, Laviolette M, Cohn L, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J. 2017;50(2).

Svenningsen S, Nair P. Asthma endotypes and an overview of targeted therapy for asthma. Front Med. 2017;4:158.

NIH-National Cancer Institute [Internet]. https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/phenotype. Accessed October 1, 2018.

Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107-1119.

Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89-95.

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.

Pizzichini E, Pizzichini MMM, Leigh R, Djukanović R, Sterk PJ. Safety of sputum induction. Eur Respir J Suppl. 2002;37:9s-18s.

van Bragt JJMH, Vijverberg SJH, Weersink EJM, et al. Blood biomarkers in chronic airways diseases and their role in diagnosis and management. Expert Rev Respir Med. 2018;12(5):361-374.

Kostikas K, Papaioannou AI, Tanou K, et al. Exhaled NO and exhaled breath condensate pH in the evaluation of asthma control. Respir Med. 2011;105(4):526-532.

New insights into the pathophysiology and therapeutic targets of asthma and comorbid chronic rhinosinusitis with or without nasal polyposis

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