Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease. In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab)/anti-IL5R (benralizumab), anti-IL-4R-α (anti-IL-4/IL-13, dupilumab), and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons.

1st Respiratory Medicine Department National and Kapodistrian University of Athens Athens Greece

Department of Clinical and Transplant Immunology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Clinical Immunology and Allergology University Hospital in Martin Slovakia

Department of Clinical Pharmacy and Pharmacology University of Groningen University Medical Center Groningen Groningen Netherlands

Department of Microbiology Immunology and Transplantation KU Leuven Catholic University of Leuven Belgium

Department of Pediatrics Jessenius Faculty of Medicine in Martin Comenius University in Bratislava University Hospital in Martin Slovakia

Department of Pulmonary Medicine Amsterdam University Medical Centers University of Amsterdam the Netherlands

Department of Pulmonology and Phthisiology Jessenius Faculty of Medicine in Martin Comenius University in Bratislava University Hospital in Martin Slovakia

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

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

Department of Respiratory Medicine National and Kapodistrian University of Athens Athens Greece

Institute of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University Prague Czech Republic

Section of Pulmonary and Critical Care Medicine Baylor College of Medicine Houston TX USA

Subdivision of Allergology and Clinical Immunology Institute for Postgraduate Education in Medicine Prague Czech Republic

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Clin Sci (Lond). 2023 Aug 16;137(15):1209. doi: 10.1042/CS-2019-0281C_COR. PubMed

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Chipps B.E., Murphy K.R. and Oppenheimer J. (2022) 2020 NAEPP Guidelines Update and GINA 2021-Asthma Care Differences, Overlap, and Challenges. J. Allergy Clin. Immunol. Pract. 10, S19–S30 10.1016/j.jaip.2021.10.032 PubMed DOI

De Prins L., Raap U., Mueller T., Schmid-Grendelmeier P., Haase C.H., Backer V.et al. . (2022) White Paper on European Patient Needs and Suggestions on Chronic Type 2 Inflammation of Airways and Skin by EUFOREA. Front Allergy 3, 889221 10.3389/falgy.2022.889221 PubMed DOI PMC

Berankova K., Uhlik J., Honkova L. and Pohunek P. (2014) Structural changes in the bronchial mucosa of young children at risk of developing asthma. Pediatr. Allergy Immunol. 25, 136–142 10.1111/pai.12119 PubMed DOI

Busse W.W. (2010) The relationship of airway hyperresponsiveness and airway inflammation: Airway hyperresponsiveness in asthma: its measurement and clinical significance. Chest 138, 4S–10S 10.1378/chest.10-0100 PubMed DOI PMC

Janulaityte I., Januskevicius A., Rimkunas A., Palacionyte J., Vitkauskiene A. and Malakauskas K. (2022) Asthmatic eosinophils alter the gene expression of extracellular matrix proteins in airway smooth muscle cells and pulmonary fibroblasts. Int. J. Mol. Sci. 23, 4086 10.3390/ijms23084086 PubMed DOI PMC

Tliba O. and Panettieri R.A. Jr (2019) Paucigranulocytic asthma: uncoupling of airway obstruction from inflammation. J. Allergy Clin. Immunol. 143, 1287–1294 10.1016/j.jaci.2018.06.008 PubMed DOI PMC

Diamant Z., Boot J.D., Mantzouranis E., Flohr R., Sterk P.J. and Gerth van Wijk R. (2010) Biomarkers in asthma and allergic rhinitis. Pulm. Pharmacol. Ther. 23, 468–481 10.1016/j.pupt.2010.06.006 PubMed DOI

Thamrin C., Frey U., Kaminsky D.A., Reddel H.K., Seely A.J., Suki B.et al. . (2016) Systems biology and clinical practice in respiratory medicine. The Twain Shall Meet. Am. J. Respir. Crit. Care Med. 194, 1053–1061 10.1164/rccm.201511-2288PP PubMed DOI PMC

Silkoff P.E., Moore W.C. and Sterk P.J. (2019) Three major efforts to phenotype asthma: severe asthma research program, asthma disease endotyping for personalized therapeutics, and unbiased biomarkers for the prediction of respiratory disease outcome. Clin. Chest Med. 40, 13–28 10.1016/j.ccm.2018.10.016 PubMed DOI

Wenzel S.E. (2012) Asthma phenotypes: the evolution from clinical to molecular approaches. Nat. Med. 18, 716–725 10.1038/nm.2678 PubMed DOI

Woodruff P.G., Modrek B., Choy D.F., Jia G., Abbas A.R., Ellwanger A.et al. . (2009) T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am. J. Respir. Crit. Care Med. 180, 388–395 10.1164/rccm.200903-0392OC PubMed DOI PMC

Hammad H. and Lambrecht B.N. (2021) The basic immunology of asthma. Cell 184, 1469–1485 10.1016/j.cell.2021.02.016 PubMed DOI

de Groot J.C., Ten Brinke A. and Bel E.H. (2015) Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res. 1, 00024–2015 10.1183/23120541.00024-2015 PubMed DOI PMC

Green R.H., Brightling C.E., McKenna S., Hargadon B., Parker D., Bradding P.et al. . (2002) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360, 1715–1721 10.1016/S0140-6736(02)11679-5 PubMed DOI

Frossing L., Silberbrandt A., Von Bulow A., Backer V. and Porsbjerg C. (2021) The prevalence of subtypes of type 2 inflammation in an unselected population of patients with severe asthma. J. Allergy Clin. Immunol. Pract. 9, 1267–1275 10.1016/j.jaip.2020.09.051 PubMed DOI

Fokkens W.J., Lund V., Bachert C., Mullol J., Bjermer L., Bousquet J.et al. . (2019) EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy 74, 2312–2319 10.1111/all.13875 PubMed DOI PMC

Fokkens W.J., Lund V.J., Hopkins C., Hellings P.W., Kern R., Reitsma S.et al. . (2020) European position paper on rhinosinusitis and nasal polyps 2020. Rhinology 58, 1–464 10.4193/Rhin20.401 PubMed DOI

Matucci A., Bormioli S., Nencini F., Chiccoli F., Vivarelli E., Maggi E.et al. . (2021) Asthma and chronic rhinosinusitis: how similar are they in pathogenesis and treatment responses? Int. J. Mol. Sci. 22, 3340 10.3390/ijms22073340 PubMed DOI PMC

Diamant Z., Vijverberg S., Alving K., Bakirtas A., Bjermer L., Custovic A.et al. . (2019) Toward clinically applicable biomarkers for asthma: An EAACI position paper. Allergy 74, 1835–1851 10.1111/all.13806 PubMed DOI

Alving K., Diamant Z., Lucas S., Magnussen H., Pavord I.D., Piacentini G.et al. . (2020) Point-of-care biomarkers in asthma management: time to move forward. Allergy 75, 995–997 10.1111/all.14045 PubMed DOI

Khatri S.B., Iaccarino J.M., Barochia A., Soghier I., Akuthota P., Brady A.et al. . (2021) Use of fractional exhaled nitric oxide to guide the treatment of asthma: an official american thoracic society clinical practice guideline. Am. J. Respir. Crit. Care Med. 204, e97–e109 10.1164/rccm.202109-2093ST PubMed DOI PMC

Moore W.C., Bleecker E.R., Curran-Everett D., Erzurum S.C., Ameredes B.T., Bacharier L.et al. . (2007) Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. J. Allergy Clin. Immunol. 119, 405–413 10.1016/j.jaci.2006.11.639 PubMed DOI PMC

Bourdin A., Bjermer L., Brightling C., Brusselle G.G., Chanez P., Chung K.F.et al. . (2019) ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions. Eur. Respir. J. 54, 1900900 10.1183/13993003.00900-2019 PubMed DOI

O'Byrne P.M., Pedersen S., Lamm C.J., Tan W.C., Busse W.W. and Group SI (2009) Severe exacerbations and decline in lung function in asthma. Am. J. Respir. Crit. Care Med. 179, 19–24 10.1164/rccm.200807-1126OC PubMed DOI

Sze E., Bhalla A. and Nair P. (2020) Mechanisms and therapeutic strategies for non-T2 asthma. Allergy 75, 311–325 10.1111/all.13985 PubMed DOI

Barnes P.J. (2017) Cellular and molecular mechanisms of asthma and COPD. Clin. Sci. (Lond.) 131, 1541–1558 10.1042/CS20160487 PubMed DOI

Papi A., Brightling C., Pedersen S.E. and Reddel H.K. (2018), Asthma Lancet 391, 783–800 10.1016/S0140-6736(17)33311-1 PubMed DOI

Stevens W.W., Lee R.J., Schleimer R.P. and Cohen N.A. (2015) Chronic rhinosinusitis pathogenesis. J. Allergy Clin. Immunol. 136, 1442–1453 10.1016/j.jaci.2015.10.009 PubMed DOI PMC

Poposki J.A., Klingler A.I., Stevens W.W., Suh L.A., Tan B.K., Peters A.T.et al. . (2022) Elevation of activated neutrophils in chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 149, 1666–1674 10.1016/j.jaci.2021.11.023 PubMed DOI PMC

Wenzel S.E. (2006) Asthma: defining of the persistent adult phenotypes. Lancet 368, 804–813 10.1016/S0140-6736(06)69290-8 PubMed DOI

Lambrecht B.N. and Hammad H. (2015) The immunology of asthma. Nat. Immunol. 16, 45–56 10.1038/ni.3049 PubMed DOI

Wawrzyniak P., Wawrzyniak M., Wanke K., Sokolowska M., Bendelja K., Ruckert B.et al. . (2017) Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients. J. Allergy Clin. Immunol. 139, 93–103 10.1016/j.jaci.2016.03.050 PubMed DOI

Sweerus K., Lachowicz-Scroggins M., Gordon E., LaFemina M., Huang X., Parikh M.et al. . (2017) Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J. Allergy Clin. Immunol. 139, 72e1–81e1 10.1016/j.jaci.2016.02.035 PubMed DOI PMC

Heijink I.H., Kies P.M., Kauffman H.F., Postma D.S., van Oosterhout A.J. and Vellenga E. (2007) Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity. J. Immunol. 178, 7678–7685 10.4049/jimmunol.178.12.7678 PubMed DOI

Wagener A.H., Zwinderman A.H., Luiten S., Fokkens W.J., Bel E.H., Sterk P.J.et al. . (2014) dsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls. Respir. Res. 15, 9 10.1186/1465-9921-15-9 PubMed DOI PMC

Golebski K., Roschmann K.I., Toppila-Salmi S., Hammad H., Lambrecht B.N., Renkonen R.et al. . (2013) The multi-faceted role of allergen exposure to the local airway mucosa. Allergy 68, 152–160 10.1111/all.12080 PubMed DOI

Gandhi V.D. and Vliagoftis H. (2015) Airway epithelium interactions with aeroallergens: role of secreted cytokines and chemokines in innate immunity. Front Immunol. 6, 147 10.3389/fimmu.2015.00147 PubMed DOI PMC

Yu Q.N., Tan W.P., Fan X.L., Guo Y.B., Qin Z.L., Li C.L.et al. . (2018) Increased Group 2 innate lymphoid cells are correlated with eosinophilic granulocytes in patients with allergic airway inflammation. Int. Arch Allergy Immunol. 176, 124–132 10.1159/000488050 PubMed DOI

van der Ploeg E.K., Golebski K., van Nimwegen M., Fergusson J.R., Heesters B.A., Martinez-Gonzalez I.et al. . (2021) Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases. Sci. Immunol. 6, eabd3489 10.1126/sciimmunol.abd3489 PubMed DOI

Weston C.A., Rana B.M.J. and Cousins D.J. (2019) Differential expression of functional chemokine receptors on human blood and lung group 2 innate lymphoid cells. J. Allergy Clin. Immunol. 143, 410e9–413e9 10.1016/j.jaci.2018.08.030 PubMed DOI PMC

Chen R., Smith S.G., Salter B., El-Gammal A., Oliveria J.P., Obminski C.et al. . (2017) Allergen-induced Increases in Sputum Levels of Group 2 Innate Lymphoid Cells in Subjects with Asthma. Am. J. Respir. Crit. Care Med. 196, 700–712 10.1164/rccm.201612-2427OC PubMed DOI

Fajt M.L., Gelhaus S.L., Freeman B., Uvalle C.E., Trudeau J.B., Holguin F.et al. . (2013) Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J. Allergy Clin. Immunol. 131, 1504–1512 10.1016/j.jaci.2013.01.035 PubMed DOI PMC

McDowell P.J. and Heaney L.G. (2020) Different endotypes and phenotypes drive the heterogeneity in severe asthma. Allergy 75, 302–310 10.1111/all.13966 PubMed DOI

Simpson J.L., Grissell T.V., Douwes J., Scott R.J., Boyle M.J. and Gibson P.G. (2007) Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax 62, 211–218 10.1136/thx.2006.061358 PubMed DOI PMC

Kyriakopoulos C., Gogali A., Bartziokas K. and Kostikas K. (2021) Identification and treatment of T2-low asthma in the era of biologics. ERJ Open Res. 7, 00309–2020 10.1183/23120541.00309-2020 PubMed DOI PMC

Ito K., Chung K.F. and Adcock I.M. (2006) Update on glucocorticoid action and resistance. J. Allergy Clin. Immunol. 117, 522–543 10.1016/j.jaci.2006.01.032 PubMed DOI

Adcock I.M., Ford P.A., Bhavsar P., Ahmad T. and Chung K.F. (2008) Steroid resistance in asthma: mechanisms and treatment options. Curr. Allergy Asthma Rep. 8, 171–178 10.1007/s11882-008-0028-4 PubMed DOI

Loke T.K., Mallett K.H., Ratoff J., O'Connor B.J., Ying S., Meng Q.et al. . (2006) Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J. Allergy Clin. Immunol. 118, 368–375 10.1016/j.jaci.2006.04.055 PubMed DOI

Adcock I.M. and Lane S.J. (2003) Corticosteroid-insensitive asthma: molecular mechanisms. J. Endocrinol. 178, 347–355 10.1677/joe.0.1780347 PubMed DOI

Kuruvilla M.E., Lee F.E. and Lee G.B. (2019) Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease. Clin. Rev. Allergy Immunol. 56, 219–233 10.1007/s12016-018-8712-1 PubMed DOI PMC

van Helden M.J. and Lambrecht B.N. (2013) Dendritic cells in asthma. Curr. Opin. Immunol. 25, 745–754 10.1016/j.coi.2013.10.002 PubMed DOI

Lu Y., Kared H., Tan S.W., Becht E., Newell E.W., Van Bever H.P.S.et al. . (2018) Dynamics of helper CD4 T cells during acute and stable allergic asthma. Mucosal. Immunol. 11, 1640–1652 10.1038/s41385-018-0057-9 PubMed DOI

Muehling L.M., Lawrence M.G. and Woodfolk J.A. (2017) Pathogenic CD4(+) T cells in patients with asthma. J. Allergy Clin. Immunol. 140, 1523–1540 10.1016/j.jaci.2017.02.025 PubMed DOI PMC

Hondowicz B.D., An D., Schenkel J.M., Kim K.S., Steach H.R., Krishnamurty A.T.et al. . (2016) Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity 44, 155–166 10.1016/j.immuni.2015.11.004 PubMed DOI PMC

Domvri K., Porpodis K., Tzimagiorgis G., Chatzopoulou F., Kontakiotis T., Kyriazis G.et al. . (2019) Th2/Th17 cytokine profile in phenotyped Greek asthmatics and relationship to biomarkers of inflammation. Respir. Med. 151, 102–110 10.1016/j.rmed.2019.03.017 PubMed DOI

Irvin C., Zafar I., Good J., Rollins D., Christianson C., Gorska M.M.et al. . (2014) Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J. Allergy Clin. Immunol. 134, 1175e7–1186e7 10.1016/j.jaci.2014.05.038 PubMed DOI PMC

Brussino L., Heffler E., Bucca C., Nicola S. and Rolla G. (2018) Eosinophils target therapy for severe asthma: critical points. Biomed. Res. Int. 2018, 7582057 10.1155/2018/7582057 PubMed DOI PMC

Durrani S.R., Viswanathan R.K. and Busse W.W. (2011) What effect does asthma treatment have on airway remodeling? Current perspectives J. Allergy Clin. Immunol. 128, 439–448, quiz 49-50 10.1016/j.jaci.2011.06.002 PubMed DOI

Bal S.M., Bernink J.H., Nagasawa M., Groot J., Shikhagaie M.M., Golebski K.et al. . (2016) IL-1beta, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat. Immunol. 17, 636–645 10.1038/ni.3444 PubMed DOI

Pelly V.S., Kannan Y., Coomes S.M., Entwistle L.J., Ruckerl D., Seddon B.et al. . (2016) IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol. 9, 1407–1417 10.1038/mi.2016.4 PubMed DOI PMC

Mendez-Enriquez E. and Hallgren J. (2019) Mast cells and their progenitors in allergic asthma. Front. Immunol. 10, 821 10.3389/fimmu.2019.00821 PubMed DOI PMC

Kim B.S., Wang K., Siracusa M.C., Saenz S.A., Brestoff J.R., Monticelli L.A.et al. . (2014) Basophils promote innate lymphoid cell responses in inflamed skin. J. Immunol. 193, 3717–3725 10.4049/jimmunol.1401307 PubMed DOI PMC

Inclan-Rico J.M., Ponessa J.J., Valero-Pacheco N., Hernandez C.M., Sy C.B., Lemenze A.D.et al. . (2020) Basophils prime group 2 innate lymphoid cells for neuropeptide-mediated inhibition. Nat. Immunol. 21, 1181–1193 10.1038/s41590-020-0753-y PubMed DOI PMC

Gibson P.G., Simpson J.L., Hankin R., Powell H. and Henry R.L. (2003) Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma. Thorax 58, 116–121 10.1136/thorax.58.2.116 PubMed DOI PMC

Hu Y., Chen Z., Zeng J., Zheng S., Sun L., Zhu L.et al. . (2020) Th17/Treg imbalance is associated with reduced indoleamine 2,3 dioxygenase activity in childhood allergic asthma. Allergy Asthma Clin. Immunol. 16, 61 10.1186/s13223-020-00457-7 PubMed DOI PMC

Palmer J.N., Messina J.C., Biletch R., Grosel K. and Mahmoud R.A. (2019) A cross-sectional, population-based survey of U.S. adults with symptoms of chronic rhinosinusitis. Allergy Asthma Proc. 40, 48–56 10.2500/aap.2019.40.4182 PubMed DOI

Passali D., Cingi C., Cambi J., Passali F., Muluk N.B. and Bellussi M.L. (2016) A survey on chronic rhinosinusitis: opinions from experts of 50 countries. Eur. Arch. Otorhinolaryngol. 273, 2097–2109 10.1007/s00405-015-3880-6 PubMed DOI

Hellings P.W. and Steelant B. (2020) Epithelial barriers in allergy and asthma. J. Allergy Clin. Immunol. 145, 1499–1509 10.1016/j.jaci.2020.04.010 PubMed DOI PMC

Peters A.T., Bose S., Guo A., Li N., Benjamin M., Prickett M.et al. . (2021) Prevalence of bronchiectasis in patients with chronic rhinosinusitis in a tertiary care center. J. Allergy Clin. Immunol. Pract. 9, 3188e2–3195e2 10.1016/j.jaip.2021.04.054 PubMed DOI PMC

Ek A., Middelveld R.J., Bertilsson H., Bjerg A., Ekerljung L., Malinovschi A.et al. . (2013) Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey. Allergy 68, 1314–1321 10.1111/all.12222 PubMed DOI

Denlinger L.C., Phillips B.R., Ramratnam S., Ross K., Bhakta N.R., Cardet J.C.et al. . (2017) Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am. J. Respir. Crit. Care Med. 195, 302–313 10.1164/rccm.201602-0419OC PubMed DOI PMC

Laidlaw T.M., Mullol J., Woessner K.M., Amin N. and Mannent L.P. (2021) Chronic rhinosinusitis with nasal polyps and asthma. J. Allergy Clin. Immunol. Pract. 9, 1133–1141 10.1016/j.jaip.2020.09.063 PubMed DOI

Khan A., Vandeplas G., Huynh T.M.T., Joish V.N., Mannent L., Tomassen P.et al. . (2019) The Global Allergy and Asthma European Network (GALEN rhinosinusitis cohort: a large European cross-sectional study of chronic rhinosinusitis patients with and without nasal polyps. Rhinology 57, 32–42 10.4193/Rhin17.255 PubMed DOI

Lee R.U. and Stevenson D.D. (2011) Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol. Res. 3, 3–10 10.4168/aair.2011.3.1.3 PubMed DOI PMC

Buchheit K., Bensko J.C., Lewis E., Gakpo D. and Laidlaw T.M. (2020) The importance of timely diagnosis of aspirin-exacerbated respiratory disease for patient health and safety. World J. Otorhinolaryngol. Head Neck Surg. 6, 203–206 10.1016/j.wjorl.2020.07.003 PubMed DOI PMC

Laidlaw T.M. and Boyce J.A. (2023) Updates on immune mechanisms in aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol., 151301–309 PubMed PMC

Kato A., Schleimer R.P. and Bleier B.S. (2022) Mechanisms and pathogenesis of chronic rhinosinusitis. J. Allergy Clin. Immunol. 149, 1491–1503 10.1016/j.jaci.2022.02.016 PubMed DOI PMC

Polzehl D., Moeller P., Riechelmann H. and Perner S. (2006) Distinct features of chronic rhinosinusitis with and without nasal polyps. Allergy 61, 1275–1279 10.1111/j.1398-9995.2006.01132.x PubMed DOI

Wang X., Zhang N., Bo M., Holtappels G., Zheng M., Lou H.et al. . (2016) Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania. J. Allergy Clin. Immunol. 138, 1344–1353 10.1016/j.jaci.2016.05.041 PubMed DOI

Tomassen P., Vandeplas G., Van Zele T., Cardell L.O., Arebro J., Olze H.et al. . (2016) Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 137, 1449e4–1456e4 10.1016/j.jaci.2015.12.1324 PubMed DOI

Bachert C. and Akdis C.A. (2016) Phenotypes and emerging endotypes of chronic rhinosinusitis. J. Allergy Clin. Immunol. Pract. 4, 621–628 10.1016/j.jaip.2016.05.004 PubMed DOI

Akdis C.A., Bachert C., Cingi C., Dykewicz M.S., Hellings P.W., Naclerio R.M.et al. . (2013) Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J. Allergy Clin. Immunol. 131, 1479–1490 10.1016/j.jaci.2013.02.036 PubMed DOI PMC

Olonisakin T.F., Moore J.A., Barel S., Uribe B., Parker D., Bowers E.M.R.et al. . (2022) Fractional exhaled nitric oxide as a marker of mucosal inflammation in chronic rhinosinusitis. Am. J. Rhinol. Allergy 19458924221080260 10.1177/19458924221080260 PubMed DOI

Heath J., Hartzell L., Putt C. and Kennedy J.L. (2018) Chronic rhinosinusitis in children: pathophysiology, evaluation, and medical management. Curr. Allergy Asthma Rep. 18, 37 10.1007/s11882-018-0792-8 PubMed DOI

Hough K.P., Curtiss M.L., Blain T.J., Liu R.-M., Trevor J., Deshane J.S.et al. . (2020) Airway remodeling in asthma. Front. Med. 7, 191.Available from: https://www.frontiersin.org/article/10.3389/fmed.2020.00191 10.3389/fmed.2020.00191 PubMed DOI PMC

Erle D.J. and Sheppard D. (2014) The cell biology of asthma. J. Cell Biol. 205, 621–631 10.1083/jcb.201401050 PubMed DOI PMC

Banno A., Reddy A.T., Lakshmi S.P. and Reddy R.C. (2020) Bidirectional interaction of airway epithelial remodeling and inflammation in asthma. Clin. Sci. (Lond.) 134, 1063–1079 10.1042/CS20191309 PubMed DOI

Joseph C. and Tatler A.L. (2022) Pathobiology of airway remodeling in asthma: the emerging role of integrins. J Asthma Allergy 15, 595–610 10.2147/JAA.S267222 PubMed DOI PMC

Khalfaoui L., Symon F.A., Couillard S., Hargadon B., Chaudhuri R., Bicknell S.et al. . (2022) Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma. Allergy 77, 2974–2986 10.1111/all.15376 PubMed DOI PMC

Pavord I.D., Hanania N.A. and Corren J. (2022) Controversies in allergy: choosing a biologic for patients with severe asthma. J. Allergy Clin. Immunol. Pract. 10, 410–419 10.1016/j.jaip.2021.12.014 PubMed DOI

Lommatzsch M. and Stoll P. (2016) Novel strategies for the treatment of asthma. Allergo J. Int. 25, 11–17 10.1007/s40629-016-0093-5 PubMed DOI PMC

Heijink I.H., Kuchibhotla V.N.S., Roffel M.P., Maes T., Knight D.A., Sayers I.et al. . (2020) Epithelial cell dysfunction, a major driver of asthma development. Allergy 75, 1902–1917 10.1111/all.14421 PubMed DOI PMC

Hiemstra P.S., McCray P.B. Jr and Bals R. (2015) The innate immune function of airway epithelial cells in inflammatory lung disease. Eur. Respir. J. 45, 1150–1162 10.1183/09031936.00141514 PubMed DOI PMC

Striz I., Brabcova E., Kolesar L. and Sekerkova A. (2014) Cytokine networking of innate immunity cells: a potential target of therapy. Clin. Sci. (Lond.) 126, 593–612 10.1042/CS20130497 PubMed DOI

Laulajainen-Hongisto A., Toppila-Salmi S.K., Luukkainen A. and Kern R. (2020) Airway epithelial dynamics in allergy and related chronic inflammatory airway diseases. Front. Cell Development. Biol. 8, 204.Available from: https://www.frontiersin.org/article/10.3389/fcell.2020.00204 10.3389/fcell.2020.00204 PubMed DOI PMC

Yuksel H. and Turkeli A. (2017) Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood. Tissue Barriers 5, e1367458 10.1080/21688370.2017.1367458 PubMed DOI PMC

Wynne M., Atkinson C., Schlosser R.J. and Mulligan J.K. (2019) Contribution of epithelial cell dysfunction to the pathogenesis of chronic rhinosinusitis with nasal polyps. Am. J. Rhinol. Allergy 33, 782–790 10.1177/1945892419868588 PubMed DOI PMC

Kato A. (2019) Group 2 innate lymphoid cells in airway diseases. Chest 156, 141–149 10.1016/j.chest.2019.04.101 PubMed DOI PMC

Matsumoto H., Niimi A., Tabuena R.P., Takemura M., Ueda T., Yamaguchi M.et al. . (2007) Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough. Chest 131, 1042–1049 10.1378/chest.06-1025 PubMed DOI

Ha E.V.S. and Rogers D.F. (2016) Novel therapies to inhibit mucus synthesis and secretion in airway hypersecretory diseases. Pharmacology 97, 84–100 10.1159/000442794 PubMed DOI

Striz I. (2017) Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations. Clin. Sci. (Lond.) 131, 2241–2256 10.1042/CS20170098 PubMed DOI

Alevy Y.G., Patel A.C., Romero A.G., Patel D.A., Tucker J., Roswit W.T.et al. . (2012) IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J. Clin. Invest. 122, 4555–4568 10.1172/JCI64896 PubMed DOI PMC

Walsh K.P. and Mills K.H. (2013) Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol. 34, 521–530 10.1016/j.it.2013.07.006 PubMed DOI

Lambrecht B.N. and Hammad H. (2012) The airway epithelium in asthma. Nat. Med. 18, 684–692 10.1038/nm.2737 PubMed DOI

Patente T.A., Pinho M.P., Oliveira A.A., Evangelista G.C.M., Bergami-Santos P.C. and Barbuto J.A.M. (2019) Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front. Immunol. 9, 3176.Available from: https://www.frontiersin.org/article/10.3389/fimmu.2018.03176 10.3389/fimmu.2018.03176 PubMed DOI PMC

Gaurav R. and Agrawal D.K. (2013) Clinical view on the importance of dendritic cells in asthma. Expert Rev. Clin. Immunol. 9, 899–919 10.1586/1744666X.2013.837260 PubMed DOI PMC

Gill M.A. (2012) The role of dendritic cells in asthma. J. Allergy Clin. Immunol. 129, 889–901 10.1016/j.jaci.2012.02.028 PubMed DOI

Romagnani S. (2004) The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 112, 352–363 10.1111/j.1365-2567.2004.01925.x PubMed DOI PMC

Altmann F. (2007) The role of protein glycosylation in allergy. Int. Arch. Allergy Immunol. 142, 99–115 10.1159/000096114 PubMed DOI

Gilles S., Mariani V., Bryce M., Mueller M.J., Ring J., Behrendt H.et al. . (2009) Pollen allergens do not come alone: pollen associated lipid mediators (PALMS) shift the human immune systems towards a T(H)2-dominated response. Allergy, Asthma Clin. Immunol.: Off. J. Canadian Soc. Allergy Clin. Immunol. 5, 3 PubMed PMC

Zuyderduyn S., Sukkar M.B., Fust A., Dhaliwal S. and Burgess J.K. (2008) Treating asthma means treating airway smooth muscle cells. Eur. Respir. J. 32, 265–274, Available from: https://erj.ersjournals.com/content/erj/32/2/265.full.pdf 10.1183/09031936.00051407 PubMed DOI

Ozier A., Allard B., Bara I., Girodet P.O., Trian T., Marthan R.et al. . (2011) The pivotal role of airway smooth muscle in asthma pathophysiology. J. Allergy 2011, 7427 10.1155/2011/742710 PubMed DOI PMC

Dileepan M., Sarver A.E., Rao S.P., Panettieri R.A. Jr, Subramanian S. and Kannan M.S. (2016) MicroRNA mediated chemokine responses in human airway smooth muscle cells. PloS ONE 11, e0150842 10.1371/journal.pone.0150842 PubMed DOI PMC

Mahn K., Hirst S.J., Ying S., Holt M.R., Lavender P., Ojo O.O.et al. . (2009) Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma. Proc. Natl. Acad. Sci. 106, 10775–10780, Available from: https://www.pnas.org/content/pnas/106/26/10775.full.pdf 10.1073/pnas.0902295106 PubMed DOI PMC

Audrit K.J., Delventhal L., Aydin Ö. and Nassenstein C. (2017) The nervous system of airways and its remodeling in inflammatory lung diseases. Cell Tissue Res. 367, 571–590 10.1007/s00441-016-2559-7 PubMed DOI

Kistemaker L.E.M. and Prakash Y.S. (2019) Airway innervation and plasticity in asthma. Physiology (Bethesda). 34, 283–298 10.1152/physiol.00050.2018 PubMed DOI PMC

Undem B.J. and Carr M.J. (2002) The role of nerves in asthma. Curr. Allergy Asthma Rep. 2, 159–165 10.1007/s11882-002-0011-4 PubMed DOI

Chapman D.G. and Irvin C.G. (2015) Mechanisms of airway hyper-responsiveness in asthma: the past, present and yet to come. Clin. Exp. Allergy: J. Br. Soc. Allergy Clin. Immunol. 45, 706–719 10.1111/cea.12506 PubMed DOI PMC

Kolahian S. and Gosens R. (2012) Cholinergic regulation of airway inflammation and remodelling. J. Allergy 2012, 681258 10.1155/2012/681258 PubMed DOI PMC

Chalermwatanachai T., Vilchez-Vargas R., Holtappels G., Lacoere T., Jáuregui R., Kerckhof F.-M.et al. . (2018) Chronic rhinosinusitis with nasal polyps is characterized by dysbacteriosis of the nasal microbiota. Sci. Rep. 8, 7926 10.1038/s41598-018-26327-2 PubMed DOI PMC

Stevens W.W., Schleimer R.P. and Kern R.C. (2016) Chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. Pract. 4, 565–572 10.1016/j.jaip.2016.04.012 PubMed DOI PMC

Flood-Page P., Menzies-Gow A., Phipps S., Ying S., Wangoo A., Ludwig M.S.et al. . (2003) Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112, 1029–1036 10.1172/JCI17974 PubMed DOI PMC

Busse W.W., Melen E. and Menzies-Gow A.N. (2022) Holy Grail: the journey towards disease modification in asthma. Eur. Respir. Rev. 31, 210183 10.1183/16000617.0183-2021 PubMed DOI PMC

Hou K., Wu Z.X., Chen X.Y., Wang J.Q., Zhang D., Xiao C.et al. . (2022) Microbiota in health and diseases. Signal Transduct. Target Ther. 7, 135 10.1038/s41392-022-00974-4 PubMed DOI PMC

Turnbaugh P.J., Ridaura V.K., Faith J.J., Rey F.E., Knight R. and Gordon J.I. (2009) The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 10.1126/scitranslmed.3000322 PubMed DOI PMC

Chotirmall S.H. and Burke C.M. (2015) Aging and the microbiome: implications for asthma in the elderly? Expert Rev. Respir. Med. 9, 125–128 10.1586/17476348.2015.1002473 PubMed DOI

Vandenborght L.E., Enaud R., Urien C., Coron N., Girodet P.O., Ferreira S.et al. . (2021) Type 2-high asthma is associated with a specific indoor mycobiome and microbiome. J. Allergy Clin. Immunol. 147, 1296e6–1305e6 10.1016/j.jaci.2020.08.035 PubMed DOI PMC

Laulajainen-Hongisto A., Toppila-Salmi S.K., Luukkainen A. and Kern R. (2020) Airway epithelial dynamics in allergy and related chronic inflammatory airway diseases. Front Cell Dev Biol. 8, 204 10.3389/fcell.2020.00204 PubMed DOI PMC

Liu Y., Teo S.M., Meric G., Tang H.H.F., Zhu Q., Sanders J.G.et al. . (2023) The gut microbiome is a significant risk factor for future chronic lung disease. J. Allergy Clin. Immunol. 151, 943–952 10.1016/j.jaci.2022.12.810 PubMed DOI PMC

Stiemsma L.T., Arrieta M.C., Dimitriu P.A., Cheng J., Thorson L., Lefebvre D.L.et al. . (2016) Shifts in Lachnospira and Clostridium sp. in the 3-month stool microbiome are associated with preschool age asthma. Clin. Sci. (Lond.) 130, 2199–2207 10.1042/CS20160349 PubMed DOI

Lad N., Murphy A.M., Parenti C., Nelson C.P., Williams N.C., Sharpe G.R.et al. . (2021) Asthma and obesity: endotoxin another insult to add to injury? Clin. Sci. (Lond.) 135, 2729–2748 10.1042/CS20210790 PubMed DOI PMC

Watts A.M., West N.P., Zhang P., Smith P.K., Cripps A.W. and Cox A.J. (2021) The gut microbiome of adults with allergic rhinitis is characterised by reduced diversity and an altered abundance of key microbial taxa compared to controls. Int. Arch. Allergy Immunol. 182, 94–105 10.1159/000510536 PubMed DOI

Yamaguchi T., Nomura A., Matsubara A., Hisada T., Tamada Y., Mikami T.et al. . (2023) Effect of gut microbial composition and diversity on major inhaled allergen sensitization and onset of allergic rhinitis. Allergol Int. 72, 135–142 10.1016/j.alit.2022.06.005 PubMed DOI

Kim Y.C., Won H.K., Lee J.W., Sohn K.H., Kim M.H., Kim T.B.et al. . (2019) Staphylococcus aureus Nasal Colonization and Asthma in Adults: Systematic Review and Meta-Analysis. J. Allergy Clin. Immunol. Pract. 7, 606e9–615e9 10.1016/j.jaip.2018.08.020 PubMed DOI

Perez-Losada M., Castro-Nallar E., Laerte Boechat J., Delgado L., Azenha Rama T., Berrios-Farias V.et al. . (2023) Nasal Bacteriomes of Patients with Asthma and Allergic Rhinitis Show Unique Composition, Structure, Function and Interactions. Microorganisms 11, 10.3390/microorganisms11030683 PubMed DOI PMC

Torre E., Sola D., Caramaschi A., Mignone F., Bona E. and Fallarini S. (2022) A pilot study on clinical scores, immune cell modulation, and microbiota composition in allergic patients with rhinitis and asthma treated with a probiotic preparation. Int. Arch Allergy Immunol. 183, 186–200 10.1159/000518952 PubMed DOI

Svenningsen S. and Nair P. (2017) Asthma endotypes and an overview of targeted therapy for asthma. Front. Med. (Lausanne) 4, 158 10.3389/fmed.2017.00158 PubMed DOI PMC

Nakayama T., Lee I.T., Le W., Tsunemi Y., Borchard N.A., Zarabanda D.et al. . (2022) Inflammatory molecular endotypes of nasal polyps derived from White and Japanese populations. J. Allergy Clin. Immunol. 149, 1296e6–1308e6 10.1016/j.jaci.2021.11.017 PubMed DOI

ten Brinke A., Grootendorst D.C., Schmidt J.T., De Bruine F.T., van Buchem M.A.et al. . (2002) Chronic sinusitis in severe asthma is related to sputum eosinophilia. J. Allergy Clin. Immunol. 109, 621–626 10.1067/mai.2002.122458 PubMed DOI

Pizzichini M.M., Popov T.A., Efthimiadis A., Hussack P., Evans S., Pizzichini E.et al. . (1996) Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am. J. Respir. Crit. Care Med. 154, 866–869 10.1164/ajrccm.154.4.8887576 PubMed DOI

Berry M., Morgan A., Shaw D.E., Parker D., Green R., Brightling C.et al. . (2007) Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 62, 1043–1049 10.1136/thx.2006.073429 PubMed DOI PMC

Durrington H.J., Gioan-Tavernier G.O., Maidstone R.J., Krakowiak K., Loudon A.S.I., Blaikley J.F.et al. . (2018) Time of Day Affects Eosinophil Biomarkers in Asthma: Implications for Diagnosis and Treatment. Am. J. Respir. Crit. Care Med. 198, 1578–1581 10.1164/rccm.201807-1289LE PubMed DOI PMC

Petsky H.L., Cates C.J., Lasserson T.J., Li A.M., Turner C., Kynaston J.A.et al. . (2012) A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 67, 199–208 10.1136/thx.2010.135574 PubMed DOI

Korevaar D.A., Westerhof G.A., Wang J., Cohen J.F., Spijker R., Sterk P.J.et al. . (2015) Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir. Med. 3, 290–300 10.1016/S2213-2600(15)00050-8 PubMed DOI

Kostikas K., Zervas E. and Gaga M. (2014) Airway and systemic eosinophilia in asthma: does site matter? Eur. Respir. J. 44, 14–16 10.1183/09031936.00034514 PubMed DOI

Spector S.L. and Tan R.A. (2012) Is a single blood eosinophil count a reliable marker for “eosinophilic asthma?” J. Asthma 49, 807–810 10.3109/02770903.2012.713428 PubMed DOI

Tran T.N., Khatry D.B., Ke X., Ward C.K. and Gossage D. (2014) High blood eosinophil count is associated with more frequent asthma attacks in asthma patients. Ann. Allergy Asthma Immunol. 113, 19–24 10.1016/j.anai.2014.04.011 PubMed DOI

Chiappori A., De Ferrari L., Folli C., Mauri P., Riccio A.M. and Canonica G.W. (2015) Biomarkers and severe asthma: a critical appraisal. Clin. Mol. Allergy 13, 20 10.1186/s12948-015-0027-7 PubMed DOI PMC

Dweik R.A., Sorkness R.L., Wenzel S., Hammel J., Curran-Everett D., Comhair S.A.et al. . (2010) Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am. J. Respir. Crit. Care Med. 181, 1033–1041 10.1164/rccm.200905-0695OC PubMed DOI PMC

Pavord I.D., Afzalnia S., Menzies-Gow A. and Heaney L.G. (2017) The current and future role of biomarkers in type 2 cytokine-mediated asthma management. Clin. Exp. Allergy 47, 148–160 10.1111/cea.12881 PubMed DOI

Dweik R.A., Boggs P.B., Erzurum S.C., Irvin C.G., Leigh M.W., Lundberg J.O.et al. . (2011) An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am. J. Respir. Crit. Care Med. 184, 602–615 10.1164/rccm.9120-11ST PubMed DOI PMC

Kostikas K., Minas M., Papaioannou A.I., Papiris S. and Dweik R.A. (2011) Exhaled nitric oxide in asthma in adults: the end is the beginning? Curr. Med. Chem. 18, 1423–1431 10.2174/092986711795328436 PubMed DOI

de Vries R., Dagelet Y.W.F., Spoor P., Snoey E., Jak P.M.C., Brinkman P.et al. . (2018) Clinical and inflammatory phenotyping by breathomics in chronic airway diseases irrespective of the diagnostic label. Eur. Respir. J. 51, 10.1183/13993003.01817-2017 PubMed DOI

Fens N., van der Sluijs K.F., van de Pol M.A., Dijkhuis A., Smids B.S., van der Zee J.S.et al. . (2015) Electronic nose identifies bronchoalveolar lavage fluid eosinophils in asthma. Am. J. Respir. Crit. Care Med. 191, 1086–1088 10.1164/rccm.201411-2010LE PubMed DOI

Fontanella S., Frainay C., Murray C.S., Simpson A. and Custovic A. (2018) Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: A cross-sectional analysis within a population-based birth cohort. PLoS Med. 15, e1002691 10.1371/journal.pmed.1002691 PubMed DOI PMC

Sehra S., Yao W., Nguyen E.T., Ahyi A.N., Tuana F.M., Ahlfeld S.K.et al. . (2011) Periostin regulates goblet cell metaplasia in a model of allergic airway inflammation. J. Immunol. 186, 4959–4966 10.4049/jimmunol.1002359 PubMed DOI PMC

Blanchard C., Mingler M.K., McBride M., Putnam P.E., Collins M.H., Chang G.et al. . (2008) Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal. Immunol. 1, 289–296 10.1038/mi.2008.15 PubMed DOI PMC

Matsumoto H. (2014) Serum periostin: a novel biomarker for asthma management. Allergol Int. 63, 153–160 10.2332/allergolint.13-RAI-0678 PubMed DOI

Takahashi K., Meguro K., Kawashima H., Kashiwakuma D., Kagami S.I., Ohta S.et al. . (2019) Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics. J. Asthma 56, 236–243 10.1080/02770903.2018.1455855 PubMed DOI

Wan X.C. and Woodruff P.G. (2016) Biomarkers in severe asthma. Immunol. Allergy Clin. North Am. 36, 547–557 10.1016/j.iac.2016.03.004 PubMed DOI PMC

Carr T.F. and Kraft M. (2018) Use of biomarkers to identify phenotypes and endotypes of severeasthma. Ann. Allergy Asthma Immunol. 121, 414–420 10.1016/j.anai.2018.07.029 PubMed DOI

Tiotiu A. (2018) Biomarkers in asthma: state of the art. Asthma Res. Pract. 4, 10 10.1186/s40733-018-0047-4 PubMed DOI PMC

An J., Lee J.H., Sim J.H., Song W.J., Kwon H.S., Cho Y.S.et al. . (2020) Serum eosinophil-derived neurotoxin better reflect asthma control status than blood eosinophil counts. J. Allergy Clin. Immunol. Pract. 8, 2681e1–2688e1 10.1016/j.jaip.2020.03.035 PubMed DOI

Kim C.K., Callaway Z., Fletcher R. and Koh Y.Y. (2010) Eosinophil-derived neurotoxin in childhood asthma: correlation with disease severity. J. Asthma 47, 568–573 10.3109/02770901003792833 PubMed DOI

Tsuda T., Maeda Y., Nishide M., Koyama S., Hayama Y., Nojima S.et al. . (2019) Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity. Int. Immunol. 31, 33–40 10.1093/intimm/dxy061 PubMed DOI PMC

Lee Y., Lee J.H., Yang E.M., Kwon E., Jung C.G., Kim S.C.et al. . (2019) Serum levels of eosinophil-derived neurotoxin: a biomarker for asthma severity in adult asthmatics. Allergy Asthma Immunol. Res. 11, 394–405 10.4168/aair.2019.11.3.394 PubMed DOI PMC

Woo S.D., Luu Q.Q. and Park H.S. (2020) NSAID-exacerbated respiratory disease (NERD): from pathogenesis to improved care. Front. Pharmacol. 11, 1147 10.3389/fphar.2020.01147 PubMed DOI PMC

Daffern P.J., Muilenburg D., Hugli T.E. and Stevenson D.D. (1999) Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses. J. Allergy Clin. Immunol. 104, 559–564 10.1016/S0091-6749(99)70324-6 PubMed DOI

Park H., Choi Y., Jung C.G. and Park H.S. (2017) Potential biomarkers for NSAID-exacerbated respiratory disease. Mediators Inflamm. 2017, 8160148 10.1155/2017/8160148 PubMed DOI PMC

Choby G., Low C.M., Levy J.M., Stokken J.K., Pinheiro-Neto C., Bartemes K.et al. . (2022) Urine leukotriene E4: implications as a biomarker in chronic rhinosinusitis. Otolaryngol. Head Neck Surg. 166, 224–232 10.1177/01945998211011060 PubMed DOI

Pham D.L., Ban G.Y., Kim S.H., Shin Y.S., Ye Y.M., Chwae Y.J.et al. . (2017) Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin. Exp. Allergy 47, 57–70 10.1111/cea.12859 PubMed DOI

Decaesteker T., Seys S., Hox V., Dilissen E., Marijsse G., Manhaeghe L.et al. . (2017) Serum and sputum calprotectin, a reflection of neutrophilic airway inflammation in asthmatics after high-altitude exposure. Clin. Exp. Allergy 47, 1675–1677 10.1111/cea.13043 PubMed DOI

Hur G.Y., Ye Y.M., Yang E. and Park H.S. (2020) Serum potential biomarkers according to sputum inflammatory cell profiles in adult asthmatics. Korean J. Intern. Med. 35, 988–997 10.3904/kjim.2019.083 PubMed DOI PMC

Agache I., Ciobanu C., Agache C. and Anghel M. (2010) Increased serum IL-17 is an independent risk factor for severe asthma. Respir. Med. 104, 1131–1137 10.1016/j.rmed.2010.02.018 PubMed DOI

Norzila M.Z., Fakes K., Henry R.L., Simpson J. and Gibson P.G. (2000) Interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am. J. Respir. Crit. Care Med. 161, 769–774 10.1164/ajrccm.161.3.9809071 PubMed DOI

Silvestri M., Bontempelli M., Giacomelli M., Malerba M., Rossi G.A., Di Stefano A.et al. . (2006) High serum levels of tumour necrosis factor-alpha and interleukin-8 in severe asthma: markers of systemic inflammation? Clin. Exp. Allergy 36, 1373–1381 10.1111/j.1365-2222.2006.02502.x PubMed DOI

Berry M.A., Hargadon B., Shelley M., Parker D., Shaw D.E., Green R.H.et al. . (2006) Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354, 697–708 10.1056/NEJMoa050580 PubMed DOI

Manni M.L., Trudeau J.B., Scheller E.V., Mandalapu S., Elloso M.M., Kolls J.K.et al. . (2014) The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol. 7, 1186–1198 10.1038/mi.2014.8 PubMed DOI PMC

Yang Y., Jia M., Ou Y., Adcock I.M. and Yao X. (2020) Airway epithelial cell damage in asthma: mechanisms and biomarkers PubMed

Busse W., Corren J., Lanier B.Q., McAlary M., Fowler-Taylor A., Cioppa G.D.et al. . (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 108, 184–190 10.1067/mai.2001.117880 PubMed DOI

Djukanovic R., Wilson S.J., Kraft M., Jarjour N.N., Steel M., Chung K.F.et al. . (2004) Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am. J. Respir. Crit. Care Med. 170, 583–593 10.1164/rccm.200312-1651OC PubMed DOI

Wu Q., Yuan L., Qiu H., Wang X., Huang X., Zheng R.et al. . (2021) Efficacy and safety of omalizumab in chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 11, e047344 10.1136/bmjopen-2020-047344 PubMed DOI PMC

Trischler J., Bottoli I., Janocha R., Heusser C., Jaumont X., Lowe P.et al. . (2021) Ligelizumab treatment for severe asthma: learnings from the clinical development programme. Clin. Transl. Immunol. 10, e1255 10.1002/cti2.1255 PubMed DOI PMC

Harris J.M., Maciuca R., Bradley M.S., Cabanski C.R., Scheerens H., Lim J.et al. . (2016) A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir. Res. 17, 29 10.1186/s12931-016-0347-2 PubMed DOI PMC

Harris J.M., Cabanski C.R., Scheerens H., Samineni D., Bradley M.S., Cochran C.et al. . (2016) A randomized trial of quilizumab in adults with refractory chronic spontaneous urticaria. J. Allergy Clin. Immunol. 138, 1730–1732 10.1016/j.jaci.2016.06.023 PubMed DOI

Cohen E.S., Dobson C.L., Kack H., Wang B., Sims D.A., Lloyd C.O.et al. . (2014) A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma. MAbs 6, 756–764 10.4161/mabs.28394 PubMed DOI PMC

Sheldon E., Schwickart M., Li J., Kim K., Crouch S., Parveen S.et al. . (2016) Pharmacokinetics, Pharmacodynamics, and Safety of MEDI4212, an Anti-IgE Monoclonal Antibody, in Subjects with Atopy: A Phase I Study. Adv. Ther. 33, 225–251 10.1007/s12325-016-0287-8 PubMed DOI

Gour N. and Wills-Karp M. (2015) IL-4 and IL-13 signaling in allergic airway disease. Cytokine 75, 68–78 10.1016/j.cyto.2015.05.014 PubMed DOI PMC

Kau A.L. and Korenblat P.E. (2014) Anti-interleukin 4 and 13 for asthma treatment in the era of endotypes. Curr. Opin. Allergy Clin. Immunol. 14, 570–575 10.1097/ACI.0000000000000108 PubMed DOI PMC

Hashimoto S., Gon Y., Takeshita I., Maruoka S. and Horie T. (2001) IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. J. Allergy Clin. Immunol. 107, 1001–1008 10.1067/mai.2001.114702 PubMed DOI

Moynihan B.J., Tolloczko B., Bassam S.E., Ferraro P., Michoud M.-C., Martin J.G.et al. . (2008) IFN-γ, IL-4 and IL-13 modulate responsiveness of human airway smooth muscle cells to IL-13. Respir. Res. 9, 84 10.1186/1465-9921-9-84 PubMed DOI PMC

Le Floc'h A., Allinne J., Nagashima K., Scott G., Birchard D., Asrat S.et al. . (2020) Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy 75, 1188–1204 10.1111/all.14151 PubMed DOI PMC

Rabe K.F., Nair P., Brusselle G., Maspero J.F., Castro M., Sher L.et al. . (2018) Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N. Engl. J. Med. 378, 2475–2485 10.1056/NEJMoa1804093 PubMed DOI

Corren J., Castro M., O'Riordan T., Hanania N.A., Pavord I.D., Quirce S.et al. . (2020) Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma. J. Allergy Clin. Immunol. Pract. 8, 516–526 10.1016/j.jaip.2019.08.050 PubMed DOI

Brusselle G.G. and Koppelman G.H. (2022) Biologic therapies for severe asthma. N. Engl. J. Med. 386, 157–171 10.1056/NEJMra2032506 PubMed DOI

Castro M., Corren J., Pavord I.D., Maspero J., Wenzel S., Rabe K.F.et al. . (2018) Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N. Engl. J. Med. 378, 2486–2496 10.1056/NEJMoa1804092 PubMed DOI

Wenzel S., Castro M., Corren J., Maspero J., Wang L., Zhang B.et al. . (2016) Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388, 31–44 10.1016/S0140-6736(16)30307-5 PubMed DOI

Rabe K.F., Nair P., Brusselle G., Maspero J.F., Castro M., Sher L.et al. . (2018) Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N. Engl. J. Med. 378, 2475–2485 10.1056/NEJMoa1804093 PubMed DOI

Laidlaw T.M., Bachert C., Amin N., Desrosiers M., Hellings P.W., Mullol J.et al. . (2021) Dupilumab improves upper and lower airway disease control in chronic rhinosinusitis with nasal polyps and asthma. Ann. Allergy Asthma Immunol. 126, 584e1–592e1 10.1016/j.anai.2021.01.012 PubMed DOI

Bacharier L.B., Maspero J.F., Katelaris C.H., Fiocchi A.G., Gagnon R., de Mir I.et al. . (2021) Dupilumab in children with uncontrolled moderate-to-severe asthma. N. Engl. J. Med. 385, 2230–2240 10.1056/NEJMoa2106567 PubMed DOI

Paller A.S., Simpson E.L., Siegfried E.C., Cork M.J., Wollenberg A., Arkwright P.D.et al. . (2022) Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 400, 908–919 10.1016/S0140-6736(22)01539-2 PubMed DOI

Aceves S.S., Dellon E.S., Greenhawt M., Hirano I., Liacouras C.A. and Spergel J.M. (2022) Clinical guidance for the use of dupilumab in eosinophilic esophagitis: a yardstick. Ann. Allergy Asthma Immunol. 3, 371–378, 10.1016/j.anai.2022.12.014 PubMed DOI

Slager R.E., Otulana B.A., Hawkins G.A., Yen Y.P., Peters S.P., Wenzel S.E.et al. . (2012) IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor alpha antagonist. J. Allergy Clin. Immunol. 130, 516e4–522e4 10.1016/j.jaci.2012.03.030 PubMed DOI PMC

Corren J., Lemanske R.F., Hanania N.A., Korenblat P.E., Parsey M.V., Arron J.R.et al. . (2011) Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 10.1056/NEJMoa1106469 PubMed DOI

Hanania N.A., Korenblat P., Chapman K.R., Bateman E.D., Kopecky P., Paggiaro P.et al. . (2016) 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 Respiratory Med. 4, 781–796 10.1016/S2213-2600(16)30265-X PubMed DOI

Busse W.W., Brusselle G.G., Korn S., Kuna P., Magnan A., Cohen D.et al. . (2019) Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur. Respir. J. 53, 1800948, Available from: https://erj.ersjournals.com/content/erj/53/2/1800948.full.pdf 10.1183/13993003.00948-2018 PubMed DOI

Panettieri R.A. Jr., Sjöbring U., Péterffy A., Wessman P., Bowen K.et al. . (2018) Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respiratory Med. 6, 511–525 10.1016/S2213-2600(18)30184-X PubMed DOI

Yalcin A.D., Onbasi K., Uzun R., Herth F. and Schnabel P.A. (2020) Human(ized) monoclonal antibodies in atopic patients - state of the art. Cent Eur. J. Immunol. 45, 195–201 10.5114/ceji.2020.97909 PubMed DOI PMC

Bagnasco D., Ferrando M., Varricchi G., Passalacqua G. and Canonica G.W. (2016) A critical evaluation of Anti-IL-13 and Anti-IL-4 strategies in severe asthma. Int. Archives Allergy Immunol. 170, 122–131 10.1159/000447692 PubMed DOI

Chaker A.M., Shamji M.H., Dumitru F.A., Calderon M.A., Scadding G.W., Makatsori M.et al. . (2016) Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti-IL-4: A randomized controlled trial. J. Allergy Clin. Immunol. 137, 452e9–461e9 10.1016/j.jaci.2015.08.046 PubMed DOI

Corren J., Busse W., Meltzer E.O., Mansfield L., Bensch G., Fahrenholz J.et al. . (2010) A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am. J. Respir. Crit. Care Med. 181, 788–796 10.1164/rccm.200909-1448OC PubMed DOI

Borish L.C., Nelson H.S., Lanz M.J., Claussen L., Whitmore J.B., Agosti J.M.et al. . (1999) Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160, 1816–1823 10.1164/ajrccm.160.6.9808146 PubMed DOI

Drick N., Seeliger B., Welte T., Fuge J. and Suhling H. (2018) Anti-IL-5 therapy in patients with severe eosinophilic asthma – clinical efficacy and possible criteria for treatment response. BMC Pulmonary Med. 18, 119 10.1186/s12890-018-0689-2 PubMed DOI PMC

Bel E.H., Wenzel S.E., Thompson P.J., Prazma C.M., Keene O.N., Yancey S.W.et al. . (2014) Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 371, 1189–1197 10.1056/NEJMoa1403291 PubMed DOI

Nair P., Wenzel S., Rabe K.F., Bourdin A., Lugogo N.L., Kuna P.et al. . (2017) Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 376, 2448–2458 10.1056/NEJMoa1703501 PubMed DOI

Pavord I.D., Korn S., Howarth P., Bleecker E.R., Buhl R., Keene O.N.et al. . (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 380, 651–659 10.1016/S0140-6736(12)60988-X PubMed DOI

Lugogo N., Domingo C., Chanez P., Leigh R., Gilson M.J., Price R.G.et al. . (2016) Long-term efficacy and safety of mepolizumab in patients with severe eosinophilic asthma: a multi-center, open-label, Phase IIIb study. Clin. Ther. 38, 2058.e1–2070.e1 10.1016/j.clinthera.2016.07.010 PubMed DOI

Caminati M., Cegolon L., Vianello A., Chieco Bianchi F., Festi G., Marchi M.R.et al. . (2019) Mepolizumab for severe eosinophilic asthma: a real-world snapshot on clinical markers and timing of response. Expert Rev. Respiratory Med. 13, 1205–1212 10.1080/17476348.2019.1676734 PubMed DOI

Wechsler M.E., Akuthota P., Jayne D., Khoury P., Klion A., Langford C.A.et al. . (2017) Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N. Engl. J. Med. 376, 1921–1932 10.1056/NEJMoa1702079 PubMed DOI PMC

Rothenberg M.E., Roufosse F., Faguer S., Gleich G.J., Steinfeld J., Yancey S.W.et al. . (2022) Mepolizumab reduces hypereosinophilic syndrome flares irrespective of blood eosinophil count and interleukin-5. J. Allergy Clin. Immunol. Pract. 10, 2367e3–2374e3 10.1016/j.jaip.2022.04.037 PubMed DOI

Fokkens W.J., Mullol J., Kennedy D., Philpott C., Seccia V., Kern R.C.et al. . (2022) Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): In-depth sinus surgery analysis. Allergy 78, 812–821 10.1111/all.15434 PubMed DOI

Bachert C., Sousa A.R., Lund V.J., Scadding G.K., Gevaert P., Nasser S.et al. . (2017) Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J. Allergy Clin. Immunol. 140, 1024e14–1031e14 10.1016/j.jaci.2017.05.044 PubMed DOI

Ortega H.G., Liu M.C., Pavord I.D., Brusselle G.G., FitzGerald J.M., Chetta A.et al. . (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371, 1198–1207 10.1056/NEJMoa1403290 PubMed DOI

Castro M., Zangrilli J., Wechsler M.E., Bateman E.D., Brusselle G.G., Bardin P.et al. . (2015) Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respiratory Med. 3, 355–366 10.1016/S2213-2600(15)00042-9 PubMed DOI

Wechsler M.E., Peters S.P., Hill T.D., Ariely R., DePietro M.R., Driessen M.T.et al. . (2021) Clinical outcomes and health-care resource use associated with reslizumab treatment in adults with severe eosinophilic asthma in real-world practice. Chest 159, 1734–1746 10.1016/j.chest.2020.11.060 PubMed DOI

Gevaert P., Lang-Loidolt D., Lackner A., Stammberger H., Staudinger H., Van Zele T.et al. . (2006) Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J. Allergy Clin. Immunol. 118, 1133–1141 10.1016/j.jaci.2006.05.031 PubMed DOI

Canonica G.W., Harrison T.W., Chanez P., Menzella F., Louis R., Cosio B.G.et al. . (2022) Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis. Allergy 77, 150–161 10.1111/all.14902 PubMed DOI

Kavanagh J.E., Hearn A.P., Dhariwal J., d'Ancona G., Douiri A., Roxas C.et al. . (2021) Real-world effectiveness of benralizumab in severe eosinophilic asthma. Chest 159, 496–506 10.1016/j.chest.2020.08.2083 PubMed DOI

Bachert C., Han J.K., Desrosiers M.Y., Gevaert P., Heffler E., Hopkins C.et al. . (2022) Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 149, 1309e12–1317e12 10.1016/j.jaci.2021.08.030 PubMed DOI

Hong H., Liao S., Chen F., Yang Q. and Wang D.Y. (2020) Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation. Allergy 75, 2794–2804 10.1111/all.14526 PubMed DOI

Soumelis V. and Liu Y.J. (2020) The discovery of human TSLP as a critical epithelial cytokine in type 2 immunity and allergic disease. Nat. Immunol. 21, 1471–1473 10.1038/s41590-020-0720-7 PubMed DOI

Mullard A. (2022) FDA approves first-in-class TSLP-targeted antibody for severe asthma. Nat. Rev. Drug Discov. 21, 89 10.1038/d41573-022-00013-5 PubMed DOI

Emson C., Diver S., Chachi L., Megally A., Small C., Downie J.et al. . (2020) CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma. Respir. Res. 21, 265 10.1186/s12931-020-01513-x PubMed DOI PMC

Diver S., Khalfaoui L., Emson C., Wenzel S.E., Menzies-Gow A., Wechsler M.E.et al. . (2021) Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir. Med. 9, 1299–1312 10.1016/S2213-2600(21)00226-5 PubMed DOI

Menzies-Gow A., Corren J., Bourdin A., Chupp G., Israel E., Wechsler M.E.et al. . (2021) Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N. Engl. J. Med. 384, 1800–1809 10.1056/NEJMoa2034975 PubMed DOI

Wechsler M.E., Menzies-Gow A., Brightling C.E., Kuna P., Korn S., Welte T.et al. . (2022) Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study. Lancet Respir. Med. 10, 650–660 10.1016/S2213-2600(21)00537-3 PubMed DOI

Numazaki M., Abe M., Hanaoka K., Imamura E., Maeda M., Kimura A.et al. . (2022) ASP7266, a novel antibody against human thymic stromal lymphopoietin receptor for the treatment of allergic diseases. J. Pharmacol. Exp. Ther. 380, 26–33 10.1124/jpet.121.000686 PubMed DOI

Borish L. and Steinke J.W. (2011) Interleukin-33 in asthma: how big of a role does it play? Curr. Allergy Asthma Rep. 11, 7–11 10.1007/s11882-010-0153-8 PubMed DOI PMC

Wechsler M.E., Ruddy M.K., Pavord I.D., Israel E., Rabe K.F., Ford L.B.et al. . (2021) Efficacy and safety of itepekimab in patients with moderate-to-severe asthma. N. Engl. J. Med. 385, 1656–1668 10.1056/NEJMoa2024257 PubMed DOI

Oh C.K., Leigh R., McLaurin K.K., Kim K., Hultquist M. and Molfino N.A. (2013) A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir. Res. 14, 93 10.1186/1465-9921-14-93 PubMed DOI PMC

Bateman E.D., Guerreros A.G., Brockhaus F., Holzhauer B., Pethe A., Kay R.A.et al. . (2017) Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur. Respir. J. 50, 1700670 10.1183/13993003.00670-2017 PubMed DOI

Brightling C.E., Gaga M., Inoue H., Li J., Maspero J., Wenzel S.et al. . (2021) Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials. Lancet Respir. Med. 9, 43–56 10.1016/S2213-2600(20)30412-4 PubMed DOI

Gevaert P., Bachert C., Maspero J.F., Cuevas M., Steele D., Acharya S.et al. . (2022) Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER). J. Allergy Clin. Immunol. 10.1016/j.jaci.2021.12.759 PubMed DOI

Singh D., Cadden P., Hunter M., Pearce Collins L., Perkins M., Pettipher R.et al. . (2013) Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur. Respir. J. 41, 46–52 10.1183/09031936.00092111 PubMed DOI

Diamant Z., Sidharta P.N., Singh D., O'Connor B.J., Zuiker R., Leaker B.R.et al. . (2014) Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin. Exp. Allergy 44, 1044–1052 10.1111/cea.12357 PubMed DOI

Ratner P., Andrews C.P., Hampel F.C., Martin B., Mohar D.E., Bourrelly D.et al. . (2017) Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies. Allergy Asthma Clin. Immunol. 13, 18 10.1186/s13223-017-0183-z PubMed DOI PMC

Neighbour H., Boulet L.P., Lemiere C., Sehmi R., Leigh R., Sousa A.R.et al. . (2014) Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 44, 508–516 10.1111/cea.12244 PubMed DOI

Kabashima K., Matsumura T., Komazaki H., Kawashima M. and Nemolizumab J.P.S.G. (2020) Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N. Engl. J. Med. 383, 141–150 10.1056/NEJMoa1917006 PubMed DOI

Sidbury R., Alpizar S., Laquer V., Dhawan S., Abramovits W., Loprete L.et al. . (2022) Pharmacokinetics, safety, efficacy, and biomarker profiles during nemolizumab treatment of atopic dermatitis in adolescents. Dermatol. Ther. (Heidelb) 12, 631–642 10.1007/s13555-021-00678-7 PubMed DOI PMC

Altrichter S., Staubach P., Pasha M., Singh B., Chang A.T., Bernstein J.A.et al. . (2022) An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria. J. Allergy Clin. Immunol. 149, 1683e7–1690e7 10.1016/j.jaci.2021.12.772 PubMed DOI

O'Byrne P.M., Metev H., Puu M., Richter K., Keen C., Uddin M.et al. . (2016) Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 4, 797–806 10.1016/S2213-2600(16)30227-2 PubMed DOI

Watz H., Uddin M., Pedersen F., Kirsten A., Goldmann T., Stellmacher F.et al. . (2017) Effects of the CXCR2 antagonist AZD5069 on lung neutrophil recruitment in asthma. Pulm. Pharmacol. Ther. 45, 121–123 10.1016/j.pupt.2017.05.012 PubMed DOI

Nair P., Gaga M., Zervas E., Alagha K., Hargreave F.E., O'Byrne P.M.et al. . (2012) Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 42, 1097–1103 10.1111/j.1365-2222.2012.04014.x PubMed DOI

Busse W.W., Holgate S., Kerwin E., Chon Y., Feng J., Lin J.et al. . (2013) 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. 188, 1294–1302 10.1164/rccm.201212-2318OC PubMed DOI

Erin E.M., Leaker B.R., Nicholson G.C., Tan A.J., Green L.M., Neighbour H.et al. . (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am. J. Respir. Crit. Care Med. 174, 753–762 10.1164/rccm.200601-072OC PubMed DOI

Holgate S.T., Noonan M., Chanez P., Busse W., Dupont L., Pavord I.et al. . (2011) Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur. Respir. J. 37, 1352–1359 10.1183/09031936.00063510 PubMed DOI

Wenzel S.E., Barnes P.J., Bleecker E.R., Bousquet J., Busse W., Dahlen S.E.et al. . (2009) A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 10.1164/rccm.200809-1512OC PubMed DOI

Dixon W.G., Hyrich K.L., Watson K.D., Lunt M., Galloway J., Ustianowski A.et al. . (2010) Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann. Rheum. Dis. 69, 522–528 10.1136/ard.2009.118935 PubMed DOI PMC

Rossios C., Pavlidis S., Hoda U., Kuo C.H., Wiegman C., Russell K.et al. . (2018) Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J. Allergy Clin. Immunol. 141, 560–570 10.1016/j.jaci.2017.02.045 PubMed DOI

Godwin M.S., Reeder K.M., Garth J.M., Blackburn J.P., Jones M., Yu Z.et al. . (2019) IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation. JCI Insight 4, e129055 10.1172/jci.insight.129055 PubMed DOI PMC

Revez J.A., Bain L.M., Watson R.M., Towers M., Collins T., Killian K.J.et al. . (2019) Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics. Clin. Transl. Immunol. 8, e1044 10.1002/cti2.1044 PubMed DOI PMC

Badi Y.E., Pavel A.B., Pavlidis S., Riley J.H., Bates S., Kermani N.Z.et al. . (2022) Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma. J. Allergy Clin. Immunol. 149, 89–101 10.1016/j.jaci.2021.04.010 PubMed DOI

Guttman-Yassky E., Brunner P.M., Neumann A.U., Khattri S., Pavel A.B., Malik K.et al. . (2018) Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial. J. Am. Acad. Dermatol. 78, 872e6–881e6 10.1016/j.jaad.2018.01.016 PubMed DOI PMC

Rymut S.M., Sukumaran S., Sperinde G., Bremer M., Galanter J., Yoshida K.et al. . (2022) Dose-dependent inactivation of airway tryptase with a novel dissociating anti-tryptase antibody (MTPS9579A) in healthy participants: A randomized trial. Clin. Transl. Sci. 15, 451–463 10.1111/cts.13163 PubMed DOI PMC

Undela K., Goldsmith L., Kew K.M. and Ferrara G. (2021) Macrolides versus placebo for chronic asthma. Cochrane Database Syst. Rev. 11, CD002997. PubMed PMC

Seresirikachorn K., Kerr S.J., Aeumjaturapat S., Chusakul S., Kanjanaumporn J., Wongpiyabovorn J.et al. . (2021) Predictive factors for identifying macrolide responder in treating chronic rhinosinusitis. Rhinology 59, 284–291 10.4193/Rhin20.649 PubMed DOI

Chupp G., Kline J.N., Khatri S.B., McEvoy C., Silvestri G.A., Shifren A.et al. . (2022) Bronchial Thermoplasty in Patients With Severe Asthma at 5 Years: The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study. Chest 161, 614–628 10.1016/j.chest.2021.10.044 PubMed DOI

Schroder A., Lunding L.P., Zissler U.M., Vock C., Webering S., Ehlers J.C.et al. . (2022) IL-37 regulates allergic inflammation by counterbalancing pro-inflammatory IL-1 and IL-33. Allergy 77, 856–869 10.1111/all.15072 PubMed DOI

Minshall E., Chakir J., Laviolette M., Molet S., Zhu Z., Olivenstein R.et al. . (2000) IL-11 expression is increased in severe asthma: association with epithelial cells and eosinophils. J. Allergy Clin. Immunol. 105, 232–238 10.1016/S0091-6749(00)90070-8 PubMed DOI

Krammer S., Yang Z., Zimmermann T., Xepapadaki P., Geppert C.I., Papadopoulos N.G.et al. . (2022) An Immunoregulatory Role of Interleukin-3 in Allergic Asthma. Front Immunol. 13, 821658 10.3389/fimmu.2022.821658 PubMed DOI PMC

Gao X., Leung T.F., Wong G.W., Ko W.H., Cai M., He E.J.et al. . (2022) Meteorin-beta/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma. Cell Mol. Immunol. 19, 245–259 10.1038/s41423-021-00803-8 PubMed DOI PMC

Johnson M.T., Xin P., Benson J.C., Pathak T., Walter V., Emrich S.M.et al. . (2022) STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma. Proc. Natl. Acad. Sci. U. S. A. 119, e2114557118 10.1073/pnas.2114557118 PubMed DOI PMC

Lunding L.P., Skouras D.B., Vock C., Dinarello C.A. and Wegmann M. (2022) The NLRP3 inflammasome inhibitor, OLT1177((R)), ameliorates experimental allergic asthma in mice. Allergy 77, 1035–1038 10.1111/all.15164 PubMed DOI

Echeverri Tirado L.C., Ghonim M.A., Wang J., Al-Khami A.A., Wyczechowska D., Luu H.H.et al. . (2019) PARP-1 is critical for recruitment of dendritic cells to the lung in a mouse model of asthma but dispensable for their differentiation and function. Mediators Inflamm. 2019, 1656484 10.1155/2019/1656484 PubMed DOI PMC

Ghonim M.A., Pyakurel K., Ibba S.V., Wang J., Rodriguez P., Al-Khami A.A.et al. . (2015) PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice. Clin. Sci. (Lond.) 129, 951–962 10.1042/CS20150122 PubMed DOI PMC

Shafiei-Jahani P., Helou D.G., Hurrell B.P., Howard E., Quach C., Painter J.D.et al. . (2021) CD200-CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma. Nat. Commun. 12, 2526 10.1038/s41467-021-22832-7 PubMed DOI PMC

Gracias D.T., Sethi G.S., Mehta A.K., Miki H., Gupta R.K., Yagita H.et al. . (2021) Combination blockade of OX40L and CD30L inhibits allergen-driven memory TH2 cell reactivity and lung inflammation. J. Allergy Clin. Immunol. 147, 2316–2329 10.1016/j.jaci.2020.10.037 PubMed DOI PMC

Powell W.S. (2021) Eicosanoid receptors as therapeutic targets for asthma. Clin. Sci. (Lond.) 135, 1945–1980 10.1042/CS20190657 PubMed DOI

Diamant Z., Aalders W., Parulekar A., Bjermer L. and Hanania N.A. (2019) Targeting lipid mediators in asthma: time for reappraisal. Curr. Opin. Pulm. Med. 25, 121–127 10.1097/MCP.0000000000000544 PubMed DOI

Werder R.B., Ullah M.A., Rahman M.M., Simpson J., Lynch J.P., Collinson N.et al. . (2022) Targeting the P2Y13 Receptor Suppresses IL-33 and HMGB1 Release and Ameliorates Experimental Asthma. Am. J. Respir. Crit. Care Med. 205, 300–312 10.1164/rccm.202009-3686OC PubMed DOI

Pivniouk V., Gimenes-Junior J.A., Ezeh P., Michael A., Pivniouk O., Hahn S.et al. . (2022) Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis. J. Allergy Clin. Immunol. 149, 943–956 10.1016/j.jaci.2021.09.013 PubMed DOI PMC

Kim J.S., Jeong J.S., Kwon S.H., Kim S.R. and Lee Y.C. (2020) Roles of PI3K pan-inhibitors and PI3K-delta inhibitors in allergic lung inflammation: a systematic review and meta-analysis. Sci. Rep. 10, 7608 10.1038/s41598-020-64594-0 PubMed DOI PMC

Sadiq M.W., Asimus S., Belvisi M.G., Brailsford W., Fransson R., Fuhr R.et al. . (2022) Characterisation of pharmacokinetics, safety and tolerability in a first-in-human study for AZD8154, a novel inhaled selective PI3Kgammadelta dual inhibitor targeting airway inflammatory disease. Br. J. Clin. Pharmacol. 88, 260–270 10.1111/bcp.14956 PubMed DOI

Pennington L.F., Gasser P., Brigger D., Guntern P., Eggel A. and Jardetzky T.S. (2021) Structure-guided design of ultrapotent disruptive IgE inhibitors to rapidly terminate acute allergic reactions. J. Allergy Clin. Immunol. 148, 1049–1060 10.1016/j.jaci.2021.03.050 PubMed DOI PMC

Canas J.A., Rodrigo-Munoz J.M., Sastre B., Gil-Martinez M., Redondo N. and Del Pozo V. (2020) MicroRNAs as potential regulators of immune response networks in asthma and chronic obstructive pulmonary disease. Front. Immunol. 11, 608666 10.3389/fimmu.2020.608666 PubMed DOI PMC

Carrer M., Crosby J.R., Sun G., Zhao C., Damle S.S., Kuntz S.G.et al. . (2020) Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite-induced Goblet Cell Metaplasia in the Adult Murine Lung. Am. J. Respir. Cell Mol. Biol. 63, 46–56 10.1165/rcmb.2019-0257OC PubMed DOI

St-Germain O., Lachapelle P., Pavord I.D. and Couillard S. (2022) Tackling ‘People Remodelling’ in Corticosteroid-dependent Asthma with Type-2 Targeting Biologics and a Formal Corticosteroid Weaning Protocol. touchrev. Respir. Pulmon. Dis. 7, 44–47 10.17925/USRPD.2022.7.2.44 DOI

Roth-Walter F., Adcock I.M., Benito-Villalvilla C., Bianchini R., Bjermer L., Caramori G.et al. . (2019) Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper. Allergy 74, 432–448 10.1111/all.13642 PubMed DOI

Thomas D., McDonald V.M., Pavord I.D. and Gibson P.G. (2022) Asthma remission: what is it and how can it be achieved? Eur. Respir. J. 60, 2102583 10.1183/13993003.02583-2021 PubMed DOI PMC

Ntontsi P., Loukides S., Bakakos P., Kostikas K., Papatheodorou G., Papathanassiou E.et al. . (2017) Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: Comparison with different sputum phenotypes. Allergy 72, 1761–1767 10.1111/all.13184 PubMed DOI

Agusti A., Bafadhel M., Beasley R., Bel E.H., Faner R., Gibson P.G.et al. . (2017) Precision medicine in airway diseases: moving to clinical practice. Eur. Respir. J. 50, 1701655 10.1183/13993003.01655-2017 PubMed DOI

Hinks T.S.C., Levine S.J. and Brusselle G.G. (2021) Treatment options in type-2 low asthma. Eur. Respir. J. 57, 2000528 10.1183/13993003.00528-2020 PubMed DOI PMC

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