INTRODUCTION: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add-on intervention to pharmacological treatment. AIT is a treatment with disease-modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. METHODS: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. RESULTS: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. CONCLUSION: This EAACI-PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT.

ALL MED Medical Research Institute Wroclaw Poland

Allergy Department 2nd Pediatric Clinic University of Athens Athens Greece

Charite Universitatsmedizin Berlin Campus Berlin Buch MASK air Montpellier France

Children's Center Bethel University Hospital Bielefeld University Bielefeld Bielefeld Germany

Department of Allergy and Clinical Immunology Royal Preston Hospital Lancashire Teaching Hospitals NHS Foundation Trust Preston UK

Department of Cardiovascular and Thoracic Sciences Università Cattolica del Sacro Cuore Rome Italy

Department of Clinical and Surgical Sciences Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italy

Department of Clinical Immunology Wroclaw Medical University Wroclaw Poland

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

Department of National Heart and Lung Institute Immunomodulation and Tolerance Group Allergy and Clinical Immunology Imperial College London London UK

Department of Otorhinolaryngology Head and Neck Surgery Section of Rhinology and Allergy University Hospital Marburg Philipps Universität Marburg Marburg Germany

Department of Pulmonology STZ Centre of Excellence for Asthma COPD and Respiratory Allergy Franciscus Gasthuis and Vlietland Rotterdam The Netherlands

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

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

Karl Landsteiner University Competence Center for Allergology and Immunology Krems Austria

MRC and Asthma UK Centre in Allergic Mechanisms of Asthma London UK

NIHR Biomedical Research Centre University Hospital Southampton NHS Foundation Trust Southampton UK

Paediatric Allergy and Respiratory Medicine Clinical and Experimental Sciences and Human Development in Health Academic Units University of Southampton Faculty of Medicine and University Hospital Southampton Southampton UK

Personalized Medicine Asthma and Allergy Clinic Humanitas University and Research Hospital IRCCS Milan Italy

School of Biological Sciences Medicine and Health University of Manchester Manchester UK

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

The David Hide Asthma and Allergy Research Centre St Mary's Hospital Newport UK

Transylvania University Brasov Romania

Zobrazit více v PubMed

Lai CK, Beasley R, Crane J, et al. Global variation in the prevalence and severity of asthma symptoms: phase three of the international study of asthma and allergies in childhood (ISAAC). Thorax. 2009;64(6):476-483.

Burney P, Jarvis D, Perez-Padilla R. The global burden of chronic respiratory disease in adults. Int J Tuberc Lung Dis. 2015;19(1):10-20.

(GINA) Gifa. Global Strategy for Asthma Management and Prevention. (GINA) Gifa; 2023.

Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J med. 2017;377(10):965-976.

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.

Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J med. 2006;355(21):2226-2235.

Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J. 2004;24(5):758-764.

Sullivan PW, Ghushchyan VH, Slejko JF, Belozeroff V, Globe DR, Lin SL. The burden of adult asthma in the United States: evidence from the medical expenditure panel survey. J Allergy Clin Immunol. 2011;127(2):363-369.e1-3.

Bernstein JA. Allergic and mixed rhinitis: epidemiology and natural history. Allergy Asthma Proc. 2010;31(5):365-369.

Martinez FD, Vercelli D. Asthma. Lancet. 2013;382(9901):1360-1372.

Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H, Sly PD. Asthma. Nat Rev Dis Primers. 2015;1:15025.

Del Giacco SR, Bakirtas A, Bel E, et al. Allergy in severe asthma. Allergy. 2017;72(2):207-220.

Agache I, Lau S, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: house dust mite-driven allergic asthma. Allergy. 2019;74(5):855-873.

Agache I, Antolin-Amerigo D, de Blay F, et al. EAACI position paper on the clinical use of the bronchial allergen challenge: unmet needs and research priorities. Allergy. 2022;77(6):1667-1684.

Pfaar O, Demoly P, Gerth van Wijk R, et al. Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI position paper. Allergy. 2014;69(7):854-867.

Jutel M, Agache I, Bonini S, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136:556-568.

Bousquet J, Van Cauwenberge P, Khaltaev N, Aria Workshop G, World Health O. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(5 Suppl):S147-S334.

Bousquet J, Khaltaev N, Cruz AA, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(Suppl 86):8-160.

Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998;102(4 Pt 1):558-562.

Shamji MH, Ljorring C, Francis JN, et al. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy. 2012;67(2):217-226.

Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J med. 1999;341(7):468-475.

Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;2007(1):CD001936.

Radulovic S, Calderon MA, Wilson D, Durham S. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2010;2010(12):CD002893.

Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011;66(6):740-752.

Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham S. Sublingual immunotherapy for treating allergic conjunctivitis. Cochrane Database Syst Rev. 2011;(7):CD007685.

Compalati E, Braido F, Canonica GW. An update on allergen immunotherapy and asthma. Curr Opin Pulm med. 2014;20(1):109-117.

Fritzsching B, Contoli M, Porsbjerg C, et al. Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: results from the REACT study, a retrospective cohort study. Lancet Reg Health Eur. 2022;13:100275.

Bousquet J, Pfaar O, Togias A, et al. 2019 ARIA Care pathways for allergen immunotherapy. Allergy. 2019;74(11):2087-2102.

Roberts G, Pfaar O, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: allergic rhinoconjunctivitis. Allergy. 2018;73(4):765-798.

Shamji MH, Durham SR. Mechanisms of immunotherapy to aeroallergens. Clin Exp Allergy. 2011;41(9):1235-1246.

Matsuoka T, Shamji MH, Durham SR. Allergen immunotherapy and tolerance. Allergol Int. 2013;62(4):403-413.

Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens. World Allergy Organ J. 2015;8(1):17.

Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol. 2014;133(3):621-631.

Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham SR. Sublingual immunotherapy for allergic conjunctivitis: Cochrane systematic review and meta-analysis. Clin Exp Allergy. 2011;41(9):1263-1272.

Lommatzsch M, Brusselle GG, Canonica GW, et al. Disease-modifying anti-asthmatic drugs. Lancet. 2022;399(10335):1664-1668.

Dhami S, Kakourou A, Asamoah F, et al. Allergen immunotherapy for allergic asthma: a systematic review and meta-analysis. Allergy. 2017;72(12):1825-1848.

Muraro R. (ed.)EAACI: Allergen Immunotherapy Guidelines Part 2: Recommendations. 2017. European Academy of Allergy and Clinical Immunology (EAACI) 2017, ISBN Number: 978-3-9524815-1-6.

Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016;47(2):410-419.

EMA. Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Asthma. EMA; 2015.

ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International conference on harmonisation E9 expert working group. Stat med. 1999;18(15):1905-1942.

Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care med. 2009;180(1):59-99.

Bourdin A, Bjermer L, Brightling C, et al. ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions. Eur Respir J. 2019;54(3):1900900.

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.

Price D, Brusselle G, Roche N, Freeman D, Chisholm A. Real-world research and its importance in respiratory medicine. Breathe (Sheff). 2015;11(1):26-38.

De Kam PJ, Kramer MF, Shamji MH, et al. Dogmas, challenges, and promises in phase III allergen immunotherapy studies. World Allergy Organ J. 2021;14(9):100578.

Guibas GV, Makris M, Papadopoulos NG. Acute asthma exacerbations in childhood: risk factors, prevention and treatment. Expert Rev Respir Med. 2012;6(6):629-638.

Incorvaia C, Ridolo E. In the strategies to prevent asthma exacerbations, allergic asthma needs specific treatment. Curr med Res Opin. 2015;31(4):821-823.

Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;2015(8):CD011293.

Wang H, Lin X, Hao C, et al. A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients. Allergy. 2006;61(2):191-197.

Devillier P, Fadel R, de Beaumont O. House dust mite sublingual immunotherapy is safe in patients with mild-to-moderate, persistent asthma: a clinical trial. Allergy. 2016;71(2):249-257.

Gomez Vera J, Flores Sandoval G, Orea Solano M, Lopez Tiro J, Jimenez SN. Safety and efficacy of specific sublingual immunotherapy in patients with asthma and allergy to Dermatophagoides pteronyssinus. Rev Alerg Mex. 2005;52(6):231-236.

Mosbech H, Canonica GW, Backer V, et al. SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms. Ann Allergy Asthma Immunol. 2015;114(2):134-140.

Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy. 2000;55(9):842-849.

Virchow JC, Backer V, Kuna P, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA. 2016;315(16):1715-1725.

O'Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J med. 2018;378(20):1865-1876.

Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;(8):CD001186.

Tanaka A, Tohda Y, Okamiya K, Azuma R, Terada I, Adachi M. Efficacy and safety of HDM SLIT tablet in Japanese adults with allergic asthma. J Allergy Clin Immunol Pract. 2020;8(2):710-720.e14.

Mosbech H, Deckelmann R, de Blay F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134(3):568-75 e7.

Wang L, Yin J, Fadel R, Montagut A, de Beaumont O, Devillier P. House dust mite sublingual immunotherapy is safe and appears to be effective in moderate, persistent asthma. Allergy. 2014;69(9):1181-1188.

Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol. 2010;126(5):942-949.

Jutel M, Rudert M, Kreimendahl F, Kuna P. Efficacy and tolerability of a house dust mite allergoid in allergic bronchial asthma: a randomized dose-ranging trial. Immunotherapy. 2018;10(13):1149-1161.

Kocks JWH, Seys SF, van Duin TS, Diamant Z, Tsiligianni IG. Assessing patient-reported outcomes in asthma and COPD patients: which can be recommended in clinical practice? Curr Opin Pulm med. 2018;24(1):18-23.

Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis. 1993;147(4):832-838.

Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the mini asthma quality of life questionnaire. Eur Respir J. 1999;14(1):32-38.

Demoly P, Bousquet PJ, Mesbah K, Bousquet J, Devillier P. Visual analogue scale in patients treated for allergic rhinitis: an observational prospective study in primary care: asthma and rhinitis. Clin Exp Allergy. 2013;43(8):881-888.

Azevedo P, Correia de Sousa J, Bousquet J, et al. Control of allergic rhinitis and asthma test (CARAT): dissemination and applications in primary care. Prim Care Respir J. 2013;22(1):112-116.

Duric-Filipovic I, Caminati M, Kostic G, Filipovic D, Zivkovic Z. Allergen specific sublingual immunotherapy in children with asthma and allergic rhinitis. World J Pediatr. 2016;12(3):283-290.

Yukselen A, Kendirli SG, Yilmaz M, Altintas DU, Karakoc GB. Effect of one-year subcutaneous and sublingual immunotherapy on clinical and laboratory parameters in children with rhinitis and asthma: a randomized, placebo-controlled, double-blind, double-dummy study. Int Arch Allergy Immunol. 2012;157(3):288-298.

Pfaar O, Nell MJ, Boot JD, et al. A randomized, 5-arm dose finding study with a mite allergoid SCIT in allergic rhinoconjunctivitis patients. Allergy. 2016;71(7):967-976.

Pfaar O, van Twuijver E, Boot JD, et al. A randomized DBPC trial to determine the optimal effective and safe dose of a SLIT-birch pollen extract for the treatment of allergic rhinitis: results of a phase II study. Allergy. 2016;71(1):99-107.

Diamant Z, Boot JD, Mantzouranis E, Flohr R, Sterk PJ, Gerth van Wijk R. Biomarkers in asthma and allergic rhinitis. Pulm Pharmacol Ther. 2010;23(6):468-481.

Eguiluz-Gracia I, Testera-Montes A, Gonzalez M, et al. Safety and reproducibility of nasal allergen challenge. Allergy. 2019;74(6):1125-1134.

Diamant Z, Gauvreau GM, Cockcroft DW, et al. Inhaled allergen bronchoprovocation tests. J Allergy Clin Immunol. 2013;132(5):1045-55 e6.

Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther. 2000;22(3):329-341.

Alvarez MJ, Echechipia S, Garcia B, et al. Liposome-entrapped D. pteronyssinus vaccination in mild asthma patients: effect of 1-year double-blind, placebo-controlled trial on inflammation, bronchial hyperresponsiveness and immediate and late bronchial responses to the allergen. Clin Exp Allergy. 2002;32(11):1574-1582.

Alexander C, Tarzi M, Larche M, Kay AB. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy. 2005;60(10):1269-1274.

Blumberga G, Groes L, Dahl R. SQ-standardized house dust mite immunotherapy as an immunomodulatory treatment in patients with asthma. Allergy. 2011;66(2):178-185.

Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol. 1999;103(4):609-614.

Gauvreau GM, Davis BE, Scadding G, et al. Allergen provocation tests in respiratory research: building on 50 years of experience. Eur Respir J. 2022;60:2102782.

Fauquert JL, Jedrzejczak-Czechowicz M, Rondon C, et al. Conjunctival allergen provocation test: guidelines for daily practice. Allergy. 2017;72(1):43-54.

Ihre E, Zetterstrom O. Increase in non-specific bronchial responsiveness after repeated inhalation of low doses of allergen. Clin Exp Allergy. 1993;23(4):298-305.

Dahlen B, Lantz AS, Ihre E, et al. Effect of formoterol with or without budesonide in repeated low-dose allergen challenge. Eur Respir J. 2009;33(4):747-753.

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(7):1035-1042.

Gauvreau GM, Watson RM, Rerecich TJ, Baswick E, Inman MD, O'Byrne PM. Repeatability of allergen-induced airway inflammation. J Allergy Clin Immunol. 1999;104(1):66-71.

Auge J, Vent J, Agache I, et al. EAACI position paper on the standardization of nasal allergen challenges. Allergy. 2018;73(8):1597-1608.

Rosner-Friese K, Kaul S, Vieths S, Pfaar O. Environmental exposure chambers in allergen immunotherapy trials: current status and clinical validation needs. J Allergy Clin Immunol. 2015;135(3):636-643.

Pfaar O, Zieglmayer P. Allergen exposure chambers: implementation in clinical trials in allergen immunotherapy. Clin Transl Allergy. 2020;10:33.

Pfaar O, Bergmann KC, Bonini S, et al. Technical standards in allergen exposure chambers worldwide - an EAACI task force report. Allergy. 2021;76(12):3589-3612.

Nolte H, Maloney J, Nelson HS, et al. Onset and dose-related efficacy of house dust mite sublingual immunotherapy tablets in an environmental exposure chamber. J Allergy Clin Immunol. 2015;135(6):1494-501 e6.

Zieglmayer P, Nolte H, Nelson HS, et al. Long-term effects of a house dust mite sublingual immunotherapy tablet in an environmental exposure chamber trial. Ann Allergy Asthma Immunol. 2016;117(6):690-696.e1.

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.

Shamji MH, Layhadi JA, Sharif H, Penagos M, Durham SR. Immunological responses and biomarkers for allergen-specific immunotherapy against inhaled allergens. J Allergy Clin Immunol Pract. 2021;9(5):1769-1778.

CHMP. EMACfMPfHU. Guideline on the Clinical Development of Products for Specific Immunotherapy for the Treatment of Allergic Diseases. CHMP; 2008.

Eifan AO, Akkoc T, Yildiz A, et al. Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial. Clin Exp Allergy. 2010;40(6):922-932.

Bahceciler NN, Arikan C, Taylor A, et al. Impact of sublingual immunotherapy on specific antibody levels in asthmatic children allergic to house dust mites. Int Arch Allergy Immunol. 2005;136(3):287-294.

Bousquet J, Scheinmann P, Guinnepain MT, et al. Sublingual-swallow immunotherapy (SLIT) in patients with asthma due to house-dust mites: a double-blind, placebo-controlled study. Allergy. 1999;54(3):249-260.

Weghofer M, Thomas WR, Kronqvist M, et al. Variability of IgE reactivity profiles among European mite allergic patients. Eur J Clin Invest. 2008;38(12):959-965.

Di Lorenzo G, Mansueto P, Pacor ML, et al. Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol. 2009;123(5):1103-1110.e4.

Li Q, Li M, Yue W, et al. Predictive factors for clinical response to allergy immunotherapy in children with asthma and rhinitis. Int Arch Allergy Immunol. 2014;164(3):210-217.

Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy Clin Immunol. 2017;140(6):1485-1498.

Rispens T, Ooijevaar-de Heer P, Bende O, Aalberse RC. Mechanism of immunoglobulin G4 fab-arm exchange. J Am Chem Soc. 2011;133(26):10302-10311.

Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002;105(1):9-19.

van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic fab arm exchange. Science. 2007;317(5844):1554-1557.

Shamji MH, Francis JN, Wurtzen PA, Lund K, Durham SR, Till SJ. Cell-free detection of allergen-IgE cross-linking with immobilized phase CD23: inhibition by blocking antibody responses after immunotherapy. J Allergy Clin Immunol. 2013;132(4):1003-1005.e4.

Bordas-Le Floch V, Berjont N, Batard T, et al. Coordinated IgG2 and IgE responses as a marker of allergen immunotherapy efficacy. Allergy. 2022;77(4):1263-1273.

Diamant Z, Vijverberg S, Alving K, et al. Toward clinically applicable biomarkers for asthma: an EAACI position paper. Allergy. 2019;74(10):1835-1851.

Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J med. 2022;386(2):157-171.

Pavord ID, Afzalnia S, Menzies-Gow A, Heaney LG. The current and future role of biomarkers in type 2 cytokine-mediated asthma management. Clin Exp Allergy. 2017;47(2):148-160.

Hoshino M, Akitsu K, Kubota K, Ohtawa J. Association between biomarkers and house dust mite sublingual immunotherapy in allergic asthma. Clin Exp Allergy. 2020;50(9):1035-1043.

Hamada S, Kobayashi Y, Sakamoto D, et al. Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis. Auris Nasus Larynx. 2021;48(4):646-652.

Hoshino M, Akitsu K, Kubota K. Effect of sublingual immunotherapy on airway inflammation and Airway Wall thickness in allergic asthma. J Allergy Clin Immunol Pract. 2019;7(8):2804-2811.

de Blay F, Gherasim A, Casale TB, Doyen V, Bernstein D. Which patients with asthma are most likely to benefit from allergen immunotherapy? J Allergy Clin Immunol. 2022;149(3):833-843.

Paoletti G, Di Bona D, Chu DK, et al. Allergen immunotherapy: the growing role of observational and randomized trial "real-world evidence". Allergy. 2021;76(9):2663-2672.

Di Bona D, Paoletti G, Chu DK, et al. Allergen immunotherapy for respiratory allergy: quality appraisal of observational comparative effectiveness studies using the REal life evidence AssessmeNt tool. An EAACI methodology committee analysis. Clin Transl. Allergy. 2021;11(4):e12033.

Fritzsching B, Contoli M, Porsbjerg C, Buchs S, Larsen JR, Freemantle N. Real-world evidence: methods for assessing long-term health and effectiveness of allergy immunotherapy. J Allergy Clin Immunol. 2022;149(3):881-883.

Anto A, Sousa-Pinto B, Bousquet J. Anaphylaxis and digital medicine. Curr Opin Allergy Clin Immunol. 2021;21:448-454.

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

Sousa-Pinto B, Sa-Sousa A, Vieira RJ, et al. Behavioural patterns in allergic rhinitis medication in Europe: a study using MASK-air((R)) real-world data. Allergy. 2022;77:2699-2711.

Bousquet J, Anto JM, Bachert C, et al. ARIA digital anamorphosis: digital transformation of health and care in airway diseases from research to practice. Allergy. 2021;76(1):168-190.

Bousquet J, Bedbrook A, Czarlewski W, et al. Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma. Clin Transl Allergy. 2019;9:16.

Sousa-Pinto B, Azevedo LF, Jutel M, et al. Development and validation of combined symptom-medication scores for allergic rhinitis. Allergy. 2021;77:2147-2162.

Sousa-Pinto B, Azevedo L, Sá-Sousa A, et al. Allergen immunotherapy in MASK-air users in real-life: results of a Bayesian mixed-effects model. Clin Transl Allergy. 2022;12:e12128.

Fonseca JA, Nogueira-Silva L, Morais-Almeida M, et al. Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma. Allergy. 2010;65(8):1042-1048.

Sousa-Pinto B, Sa-Sousa A, Amaral R, et al. Assessment of the control of allergic rhinitis and asthma test (CARAT) using MASK-air. J Allergy Clin Immunol Pract. 2022;10(1):343-5 e2.

van Dijk BCP, Svedsater H, Heddini A, Nelsen L, Balradj JS, Alleman C. Relationship between the asthma control test (ACT) and other outcomes: a targeted literature review. BMC Pulm med. 2020;20(1):79.

Shrimanker R, Keene O, Hynes G, Wenzel S, Yancey S, Pavord ID. Prognostic and predictive value of blood eosinophil count, fractional exhaled nitric oxide, and their combination in severe asthma: a post hoc analysis. Am J Respir Crit Care med. 2019;200(10):1308-1312.

Kellerer C, Hapfelmeier A, Jorres RA, Schultz K, Brunn B, Schneider A. Evaluation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) in patients with suspected asthma: study protocol for a prospective diagnostic study. BMJ Open. 2021;11(2):e045420.

Busse WW, Wenzel SE, Casale TB, et al. Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis. Lancet Respir med. 2021;9(10):1165-1173.

Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-1721.

Sont JK, Willems LN, Bel EH, van Krieken JH, 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;159(4 Pt 1):1043-1051.

Wang K, Verbakel JY, Oke J, et al. Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis. Eur Respir J. 2020;55(5):1902150.

Fuhlbrigge AL, Bengtsson T, Peterson S, et al. A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials. Lancet Respir med. 2017;5(7):577-590.

Xepapadaki P, Korovessi P, Bachert C, et al. Evolution of airway inflammation in preschoolers with asthma-results of a two-year longitudinal study. J Clin med. 2020;9(1):187.

Improvement of the therapeutic management of allergic patients in Europe - An expert think tank's position paper on allergen immunotherapy