PURPOSE OF REVIEW: Allergen bronchoprovocation test (ABT) has been used to study asthma pathophysiology and as a disease-modelling tool to assess the properties and efficacy of new asthma drugs. In view of the complexity and heterogeneity of asthma, which has driven the definition of several phenotypes and endotypes, we aim to discuss the role of ABT in the era of precision medicine and provide guidance for clinicians how to interpret and use available data to understand the implications for the benefits of asthma treatment. RECENT FINDINGS: In this review, we summarize background knowledge and applications of ABT and provide an update with recent publications on this topic. In the past years, several studies have been published on ABT in combination with non-invasive and invasive airway samplings and innovative detection techniques allowing to study several inflammatory mechanisms linked to Th2-pathway and allergen-induced pathophysiology throughout the airways. SUMMARY: ABT is a valuable research tool, which has strongly contributed to precision medicine by helping to define allergen-triggered key inflammatory pathways and airway pathophysiology, and thus helped to shape our understanding of allergen-driven asthma phenotypes and endotypes. In addition, ABT has been instrumental to assess the interactions and effects of new-targeted asthma treatments along these pathways.

Department Clinical Pharmacy and Pharmacology University Groningen University Medicine Ctr Groningen Groningen The Netherlands

Department of Medicine McMaster University Hamilton Ontario Canada

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

Institut Universitaire de Cardiologie et de Pneumologie de Québec Québec Heart and Lung Institute Université Laval Québec Canada

QPS Netherlands Groningen The Netherlands

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Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol 2019; 144:1–12.

GINA. Global initiative for asthma (GINA). 2020; www.ginasthma.orgwww.ginasthma.org . Accessed 15 September 2020.

Galli SJ. Toward precision medicine and health: opportunities and challenges in allergic diseases. J Allergy Clin Immunol 2016; 137:1289–1300.

Agusti A, Bafadhel M, Beasley R, et al. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J 2017; 50:

Diamant Z, Gauvreau GM, Cockcroft DW, et al. Inhaled allergen bronchoprovocation tests. J Allergy Clin Immunol 2013; 132:1045–1055.e6.

Boulet LP, Gauvreau G, Boulay ME, et al. The allergen bronchoprovocation model: an important tool for the investigation of new asthma anti-inflammatory therapies. Allergy 2007; 62:1101–1110.

Cockcroft DW, Hargreave FE, O’Byrne PM, et al. Understanding allergic asthma from allergen inhalation tests. Can Resp J 2007; 14:414–418.

Gauvreau GM, El-Gammal AI, O’Byrne PM. Allergen-induced airway responses. Eur Resp J 2015; 46:819–831.

Vandenplas O, Suojalehto H, Cullinan P. Diagnosing occupational asthma. Clin Exp Allergy 2017; 47:6–18.

Cockcroft DW. Allergen-induced asthma. Can Resp J 2014; 21:279–282.

Zuiker RG, Ruddy MK, Morelli N, et al. Kinetics of TH2 biomarkers in sputum of asthmatics following inhaled allergen. Eur Clin Resp J 2015; 2:

Gauvreau GM, Watson RM, Rerecich TJ, et al. Repeatability of allergen-induced airway inflammation. J Allergy Clin Immunol 1999; 104:66–71.

Pfaar O, Calderon MA, Andrews CP, et al. Allergen exposure chambers: harmonizing current concepts and projecting the needs for the future: an EAACI Position Paper. Allergy 2017; 72:1035–1042.

Yang WH, Kelly SM, Yang J, et al. Development and validation of an Allergen Challenge Theater for grass and ragweed. Allergy 2019; 74:2531–2533.

Julius P, Lommatzsch M, Kuepper M, et al. Safety of segmental allergen challenge in human allergic asthma. J Allergy Clin Immunol 2008; 121:712–717.

Stenberg H, Diamant Z, Ankerst J, et al. Small airway involvement in the late allergic response in asthma. Clin Exp Allergy 2017; 47:1555–1565.

O’Byrne PM, Naji N, Gauvreau GM. Severe asthma: future treatments. Clin Exp Allergy 2012; 42:706–711.

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

Ma LL, O’Byrne PM. The pharmacological modulation of allergen-induced asthma. Inflammopharmacology 2013; 21:113–124.

Satia I, Watson R, Scime T, et al. Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma. J Allergy Clin Immunol 2019; 144:788–795.e1.

Diamant Z, Boot JD, Mantzouranis E, et al. Biomarkers in asthma and allergic rhinitis. Pulm Pharmacol Therap 2010; 23:468–481.

Imaoka H, Gauvreau GM, Watson RM, et al. Sputum inflammatory cells and allergen-induced airway responses in allergic asthmatic subjects. Allergy 2011; 66:1075–1080.

Kinoshita T, Baatjes A, Smith SG, et al. Natural regulatory T cells in isolated early responders compared with dual responders with allergic asthma. J Allergy Clin Immunol 2014; 133:696–703.

Gauvreau GM, Doctor J, Watson RM, et al. Effects of inhaled budesonide on allergen-induced airway responses and airway inflammation. Am J Resp Crit Care Med 1996; 154:1267–1271.

Gauvreau GM, Jordana M, Watson RM, et al. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Resp Crit Care Med 1997; 156:1738–1745.

Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Resp Crit Care Med 1999; 160:640–647.

Gauvreau GM, Lee JM, Watson RM, et al. Increased numbers of both airway basophils and mast cells in sputum after allergen inhalation challenge of atopic asthmatics. Am J Resp Crit Care Med 2000; 161:1473–1478.

Dua B, Watson RM, Gauvreau GM, et al. Myeloid and plasmacytoid dendritic cells in induced sputum after allergen inhalation in subjects with asthma. J Allergy Clin Immunol 2010; 126:133–139.

Oliveria JP, El-Gammal AI, Yee M, et al. Changes in regulatory B-cell levels in bone marrow, blood, and sputum of patients with asthma following inhaled allergen challenge. J Allergy Clin Immunol 2018; 141:1495–1498.e9.

Oliveria JP, Salter BM, MacLean J, et al. Increased IgE(+) B cells in sputum, but not blood, bone marrow, or tonsils, after inhaled allergen challenge in subjects with asthma. Am J Resp Crit Care Med 2017; 196:107–109.

Tang W, Smith SG, Du W, et al. Interleukin-25 and eosinophils progenitor cell mobilization in allergic asthma. Clin Transl Allergy 2018; 8:5.

Chen R, Smith SG, Salter B, et al. Allergen-induced increases in sputum levels of group 2 innate lymphoid cells in subjects with asthma. Am J Resp Crit Care Med 2017; 196:700–712.

Tworek D, Smith SG, Salter BM, et al. IL-25 receptor expression on airway dendritic cells after allergen challenge in subjects with asthma. Am J Resp Crit Care Med 2016; 193:957–964.

Baatjes AJ, Smith SG, Dua B, et al. Treatment with anti-OX40L or anti-TSLP does not alter the frequency of T regulatory cells in allergic asthmatics. Allergy 2015; 70:1505–1508.

Machida K, Aw M, Salter BM, et al. Role of TL1A/DR3 axis in the activation of ILC2s in eosinophilic asthmatics. Am J Resp Crit Care Med 2020.

Nolin JD, Lai Y, Ogden HL, et al. Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2017; 2:

Salter BM, Nusca G, Tworek D, et al. Expression of activation markers in circulating basophils and the relationship to allergen-induced bronchoconstriction in subjects with mild allergic asthma. J Allergy Clin Immunol 2016; 137:936–938.e7.

Revez JA, Killian KJ, O’Byrne PM, et al. Sputum cytology during late-phase responses to inhalation challenge with different allergens. Allergy 2018; 73:1470–1478.

Stenberg H, Wadelius E, Moitra S, et al. Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics. Biomarkers 2018; 23:51–60.

Kalinauskaite-Zukauske V, Janulaityte I, Januskevicius A, et al. Serum levels of epithelial-derived mediators and interleukin-4/interleukin-13 signaling after bronchial challenge with Dermatophagoides pteronyssinus in patients with allergic asthma. Scand J Immunol 2019; 90:e12820.

Wang W, Li Y, Lv Z, et al. Bronchial allergen challenge of patients with atopic asthma triggers an alarmin (IL-33, TSLP, and IL-25) response in the airways epithelium and submucosa. J Immunol (Baltimore, Md: 1950) 2018; 201:2221–2231.

Al-Sajee D, Sehmi R, Hawke TJ, et al. Expression of IL-33 and TSLP and their receptors in asthmatic airways after inhaled allergen challenge. Am J Resp Crit Care Med 2018; 198:805–807.

Tang W, Smith SG, Salter B, et al. Allergen-induced increases in interleukin-25 and interleukin-25 receptor expression in mature eosinophils from atopic asthmatics. Int Arch Allergy Immunol 2016; 170:234–242.

Mitchell PD, Salter BM, Oliveria JP, et al. IL-33 and its receptor ST2 after inhaled allergen challenge in allergic asthmatics. Int Arch Allergy Immunol 2018; 176:133–142.

He D, Yang CX, Sahin B, et al. Whole blood vs PBMC: compartmental differences in gene expression profiling exemplified in asthma. Allergy, Asthma, Clin Immunol 2019; 15:67.

Rajasekaran A, He D, Yue A, et al. Cholinergic synapse pathway gene polymorphisms associated with allergen-induced late asthmatic responses. ERJ Open Res 2019; 5:

Singh A, Shannon CP, Kim YW, et al. Novel blood-based transcriptional biomarker panels predict the late-phase asthmatic response. Am J Resp Crit Care Med 2018; 197:450–462.

Singh A, Shannon CP, Kim YW, et al. Identifying molecular mechanisms of the late-phase asthmatic response by integrating cellular, gene, and metabolite levels in blood. Ann Am Thorac Soc 2016; 13: (Suppl 1): S98.

Kabata H, Moro K, Koyasu S. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms. Immunol Rev 2018; 286:37–52.

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

Peebles RS Jr, Aronica MA. Proinflammatory pathways in the pathogenesis of asthma. Clin Chest Med 2019; 40:29–50.

Smith SG, Chen R, Kjarsgaard M, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol 2016; 137:75–86.e8.

Winkler C, Hochdorfer T, Israelsson E, et al. Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients. J Allergy Clin Immunol 2019; 144:61–69.e7.

Polak D, Hafner C, Briza P, et al. A novel role for neutrophils in IgE-mediated allergy: evidence for antigen presentation in late-phase reactions. J Allergy Clin Immunol 2019; 143:1143–1152.e4.

Ekstedt S, Safholm J, Georen SK, et al. Dividing neutrophils in subsets reveals a significant role for activated neutrophils in the development of airway hyperreactivity. Clin Exp Allergy 2019; 49:285–291.

Cockcroft DW. Allergen-induced increase in nonallergic airway responsiveness: a citation classic revisited. Can Resp J 2000; 7:182–187.

Lloyd CM, Robinson DS. Allergen-induced airway remodelling. Eur Resp J 2007; 29:1020–1032.

Adams DC, Miller AJ, Applegate MB, et al. Quantitative assessment of airway remodelling and response to allergen in asthma. Respirology 2019; 24:1073–1080.

Boulet LP, Morin D, Milot J, et al. Bronchial responsiveness increases after seasonal antigen exposure in nonasthmatic subjects with pollen-induced rhinitis. Ann Allergy 1989; 63:114–119.

Naji N, Keung E, Kane J, et al. Comparison of changes in lung function measured by plethymography and IOS after bronchoprovocation. Resp Med 2013; 107:503–510.

Fahy JV, Cockcroft DW, Boulet LP, et al. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am J Resp Crit Care Med 1999; 160:1023–1027.

Boulet LP, Chapman KR, Cote J, et al. Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am J Resp Crit Care Med 1997; 155:1835–1840.

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; 95:42–51.

Diamant Z, Grootendorst DC, Veselic-Charvat M, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999; 29:42–51.

Boot JD, de Haas S, Tarasevych S, et al. Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Resp Crit Care Med 2007; 175:450–457.

Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356:2144–2148.

Kent SE, Boyce M, Diamant Z, et al. The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma. Clin Exp Allergy 2013; 43:177–186.

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; 44:1044–1052.

Diamant Z, Timmers MC, van der Veen H, et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Resp Crit Care Med 1996; 153:1790–1795.

Revez JA, Bain LM, Watson RM, et al. Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics. Clin Transl Immunol 2019; 8:e1044.

Gauvreau GM, FitzGerald JM, Boulet LP, et al. The effects of a CCR3 inhibitor, AXP1275, on allergen-induced airway responses in adults with mild-to-moderate atopic asthma. Clin Exp Allergy 2018; 48:445–451.

Gauvreau GM, Boulet LP, FitzGerald JM, et al. A dual CysLT1/2 antagonist attenuates allergen-induced airway responses in subjects with mild allergic asthma. Allergy 2016; 71:1721–1727.

Boulet LP, Gauvreau GM, Cockcroft DW, et al. Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma. Can Resp J 2015; 22:230–234.

Gauvreau GM, Boulet LP, Leigh R, et al. A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses. Am J Resp Crit Care Med 2015; 191:161–167.

Gauvreau GM, Harris JM, Boulet LP, et al. Targeting membrane-expressed IgE B cell receptor with an antibody to the M1 prime epitope reduces IgE production. Sci Transl Med 2014; 6:243ra85.

Gauvreau GM, O’Byrne PM, Boulet LP, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014; 370:2102–2110.

Gauvreau GM, Boulet LP, Cockcroft DW, et al. OX40L blockade and allergen-induced airway responses in subjects with mild asthma. Clin Exp Allergy 2014; 44:29–37.

Gauvreau GM, Sehmi R, Ambrose CS, et al. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets 2020; 1–16.

Walsh GM. Mepolizumab and eosinophil-mediated disease. Curr Med Chem 2009; 16:4774–4778.

Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360:985–993.

Ratner P, Andrews CP, Hampel FC, et al. 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 2017; 13:18.

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

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

Diamant Z, Vijverberg S, Alving K, et al. Toward clinically applicable biomarkers for asthma: an EAACI position paper. Allergy 2019; 74:1835–1851.

Changes in Small Airway Physiology Measured by Impulse Oscillometry in Subjects with Allergic Asthma Following Methacholine and Inhaled Allergen Challenge