Association between pre-biologic T2-biomarker combinations and response to  biologics in patients with severe asthma.

Biomarkers; Immunoglobulin E; Biological Products; Anti-Asthmatic Agents; 31C4KY9ESH (Nitric Oxide); Humans; Asthma/drug therapy/diagnosis/immunology; Male; Female; Middle Aged; Immunoglobulin E/blood/immunology; Adult; Eosinophils/immunology; Biological Products/therapeutic use; Anti-Asthmatic Agents/therapeutic use; Treatment Outcome; Registries; Severity of Illness Index; Leukocyte Count; Nitric Oxide/metabolism; Aged; Cohort Studies; FEV1; FeNO (Fraction of exhaled Nitric Oxide); biologics; biomarkers; eosinophil (EOS); personalized medicine (PM); severe asthma

Abstract :

[en] BACKGROUND: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. AIM: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. METHODS: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. RESULTS: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV(1) for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV(1) improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV(1) increase (adjusted R(2): 0.751), compared to BEC (adjusted R(2): 0.747) or FeNO alone (adjusted R(2): 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. CONCLUSIONS: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.

Disciplines :

Cardiovascular & respiratory systems

Author, co-author :

Porsbjerg, Celeste M; Department of Respiratory Medicine and Infectious Diseases, Research Unit, Bispebjerg Hospital, Copenhagen, Denmark.

Townend, John; Observational and Pragmatic Research Institute, Singapore, Singapore. ; Optimum Patient Care Global, Cambridge, United Kingdom.

Bergeron, Celine; Department of Medicine, Centre for Lung Health, Vancouver General Hospital, Vancouver, BC, Canada. ; Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.

Christoff, George C; Faculty of Public Health, Medical University, Sofia, Bulgaria.

Katsoulotos, Gregory P; Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia. ; School of Medicine, Sydney Campus, The University of Notre Dame, Sydney, NSW, Australia.

Larenas-Linnemann, Désirée; Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico.

Tran, Trung N; BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, United States.

Al-Lehebi, Riyad; Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia. ; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

Bosnic-Anticevich, Sinthia Z; Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia. ; Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.

Busby, John; Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.

More authors (77 more)

Language :

English

Title :

Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma.

Publication date :

19 April 2024

Journal title :

Frontiers in Immunology

eISSN :

1664-3224

Publisher :

Frontiers, Lausanne, Ch

Volume :

Pages :

1361891

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Copyright © 2024 Porsbjerg, Townend, Bergeron, Christoff, Katsoulotos, Larenas-Linnemann, Tran, Al-Lehebi, Bosnic-Anticevich, Busby, Hew, Kostikas, Papadopoulos, Pfeffer, Popov, Rhee, Sadatsafavi, Tsai, Ulrik, Al-Ahmad, Altraja, Beastall, Bulathsinhala, Carter, Cosio, Fletton, Hansen, Heaney, Hubbard, Kuna, Murray, Nagano, Pini, Cano Rosales, Schleich, Wechsler, Amaral, Bourdin, Brusselle, Chen, Chung, Denton, Fonseca, Hoyte, Jackson, Katial, Kirenga, Koh, Ławkiedraj, Lehtimäki, Liew, Mahboub, Martin, Menzies-Gow, Pang, Papaioannou, Patel, Perez-De-Llano, Peters, Ricciardi, Rodríguez-Cáceres, Solarte, Tay, Torres-Duque, Wang, Zappa, Abisheganaden, Assing, Costello, Gibson, Heffler, Máspero, Nicola, Perng (Steve), Puggioni, Salvi, Sheu, Sirena, Taillé, Tan, Bjermer, Canonica, Iwanaga, Jiménez-Maldonado, Taube, Brussino and Price.

Available on ORBi :

since 01 July 2025

Statistics

Number of views

30 (1 by ULiège)

Number of downloads

11 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Wenzel SE. Severe adult asthmas: integrating clinical features, biology, and therapeutics to improve outcomes. Am J Respir Crit Care Med. (2021) 203:809–21. doi: 10.1164/rccm.202009-3631CI
Denton E Price DB Tran TN Canonica GW Menzies-Gow A FitzGerald JM et al. Cluster analysis of inflammatory biomarker expression in the international severe asthma registry. J Allergy Clin Immunol Pract. (2021) 9:2680–2688.e7. doi: 10.1016/j.jaip.2021.02.059
Heaney LG Perez de Llano L Al-Ahmad M Backer V Busby J Canonica GW et al. Eosinophilic and non-eosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort. Chest. (2021) 160:814–30. doi: 10.1016/j.chest.2021.04.013
Busse WW Holgate ST Wenzel SW Klekotka P Chon Y Feng J et al. Biomarker profiles in asthma with high vs low airway reversibility and poor disease control. Chest. (2015) 148:1489–96. doi: 10.1378/chest.14-2457
Guida G Carriero V Bertolini F Pizzimenti S Heffler E Paoletti G et al. Exhaled nitric oxide in asthma: from diagnosis to management. Curr Opin Allergy Clin Immunol. (2023) 23:29–35. doi: 10.1097/ACI.0000000000000877
Lee LA Bailes Z Barnes N Boulet L-P Edwards D Fowler A et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med. (2021) 9:69–84. doi: 10.1016/S2213-2600(20)30389-1
Corren J Pham T-H Garcia Gil E Sałapa K Ren P Parnes JR et al. Baseline type 2 biomarker levels and response to tezepelumab in severe asthma. Allergy. (2022) 77:1786–96. doi: 10.1111/all.15197
Ortega HG Yancey SW Mayer B Gunsoy NB Keene ON Bleecker ER et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. (2016) 4:549–56. doi: 10.1016/S2213-2600(16)30031-5
Bernstein JA Virchow JC Murphy K Maspero JF Jacobs J Adir Y et al. Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir Med. (2020) 8:461–74. doi: 10.1016/S2213-2600(19)30372-8
FitzGerald JM Bleecker ER Nair P Korn S Ohta K Lommatzsch M et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. (2016) 388:2128–41. doi: 10.1016/S0140-6736(16)31322-8
Menzies-Gow A Corren J Bourdin A Chupp G Israel E Wechsler ME et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. (2021) 384:1800–9. doi: 10.1056/NEJMoa2034975
Pavord ID Deniz Y Corren J Casale TB FitzGerald JM Izuhara K et al. Baseline feNO independently predicts the dupilumab response in patients with moderate-to-severe asthma. J Allergy Clin Immunol Pract. (2023) 11:1213–1220.e2. doi: 10.1016/j.jaip.2022.11.043
Ray A Das J Wenzel SE. Determining asthma endotypes and outcomes: Complementing existing clinical practice with modern machine learning. Cell Rep Med. (2022) 3:100857. doi: 10.1016/j.xcrm.2022.100857
Busby J Khoo E Pfeffer PE Mansur AH Heaney LG. The effects of oral corticosteroids on lung function, type-2 biomarkers and patient-reported outcomes in stable asthma: A systematic review and meta-analysis. Respir Med. (2020) 173:106156. doi: 10.1016/j.rmed.2020.106156
Li H Zhang Q Wang J Gao S Li C Wang J et al. Variability of Type 2 inflammatory markers guiding biologic therapy of severe asthma: A 5-year retrospective study from a single tertiary hospital. World Allergy Organ J. (2021) 14:100547. doi: 10.1016/j.waojou.2021.100547
Sánchez J Morales E Santamaria L-C Acevedo A-M Calle A Olivares M et al. IgE, blood eosinophils and FeNO are not enough for choosing a monoclonal therapy among the approved options in patients with type 2 severe asthma. World Allergy Organ J. (2021) 14:100520. doi: 10.1016/j.waojou.2021.100520
Porsbjerg CM Menzies-Gow AN Tran TN Murray RB Unni B Audrey Ang SL et al. Global variability in administrative approval prescription criteria for biologic therapy in severe asthma. J Allergy Clin Immunol Pract. (2022) 10:1202–16. doi: 10.1016/j.jaip.2021.12.027
Diamant Z Vijverberg S Alving K Bakirtas A Bjermer L Custovic A et al. Toward clinically applicable biomarkers for asthma: An EAACI position paper. Allergy. (2019) 74:1835–51. doi: 10.1111/all.13806
Menzella F Fontana M Galeone C Ghidoni G Capobelli S Ruggiero P et al. Real world effectiveness of benralizumab on respiratory function and asthma control. Multidiscip Respir Med. (2021) 16:785. doi: 10.4081/mrm.2021.785
Wenzel S Castro M Corren J Maspero J Wang L Zhang B et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. (2016) 388:31–44. doi: 10.1016/S0140-6736(16)30307-5
Corren J Weinstein S Janka L Zangrilli J Garin M. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. (2016) 150:799–810. doi: 10.1016/j.chest.2016.03.018
Soremekun S Heaney LG Skinner D Bulathsinhala L Carter V Chaudhry I et al. Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study. Thorax. (2023) 78(7):643–52. doi: 10.1136/thorax-2021-217032
Sears MR. Lung function decline in asthma. Eur Respir J. (2007) 30:411–3. doi: 10.1183/09031936.00080007
Calhoun WJ Haselkorn T Miller DP Omachi TA. Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol. (2015) 136:1125–1127.e4. doi: 10.1016/j.jaci.2015.05.014
Perez de Llano L Scelo G Tran TN Le TT Martin N Fageras M et al. Characteristics associated with clinical remission in patients with severe asthma who initiate biologics. Eur Respir J. (2023) 62:PA1892. doi: 10.1183/13993003.congress-2023.PA1892
ISAR Study Group. International severe asthma registry (ISAR): mission statement. Chest. (2020) 157:805–14. doi: 10.1016/j.chest.2019.10.051
FitzGerald JM Tran TN Alacqua M Altraja A Backer V Bjermer L et al. International severe asthma registry (ISAR): protocol for a global registry. BMC Med Res Methodol. (2020) 20:212. doi: 10.1186/s12874-020-01065-0
Cushen B Koh MS Tran TN Martin N RB M Uthaman T. Adult severe asthma registries: a global and growing inventory. Prag Observational Res. (2023) 14:127–47. doi: 10.2147/POR.S399879
Wang E Wechsler ME Tran TN Heaney LG Jones RC Menzies-Gow AN et al. Characterization of severe asthma worldwide: data from the International Severe Asthma Registry (ISAR). Chest. (2020) 157:790–804. doi: 10.1016/j.chest.2019.10.053
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Available online at: https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf (Accessed 26th March 2024).
Global Initiative for Asthma. Global Strategy for Asthma Prevention and Treatment (2018). Available online at: https://ginasthma.org/wp-content/uploads/2019/01/2018-GINA.pdf (Accessed 26th March 2024).
Nathan RA Sorkness CA Kosinski M Schatz M Li JT Marcus P et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. (2004) 113:59–65. doi: 10.1016/j.jaci.2003.09.008
Juniper EF O’Byrne PM Guyatt GH Ferrie PJ King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. (1999) 14:902–7. doi: 10.1034/j.1399-3003.1999.14d29.x
Korn S Both J Jung M Hübner M Taube C Buhl R. Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. Ann Allergy Asthma Immunol. (2011) 107:474–9. doi: 10.1016/j.anai.2011.09.001
Koolen BB Pijnenburg MWH Brackel HJL Landstra AM van den Berg NJ Merkus PJFM et al. Comparing global initiative for asthma (GINA) criteria with the childhood asthma control test (C-ACT) and asthma control test (ACT). Eur Respir J. (2011) 38:561–6. doi: 10.1183/09031936.00173710
Canonica GW Blasi F Carpagnano GE Guida G Heffler E Paggiaro P et al. Severe asthma network Italy definition of clinical remission in severe asthma: A delphi consensus. J Allergy Clin Immunol Pract. (2023) 11(2):3629–37. doi: 10.1016/j.jaip.2023.07.041
McDowell PJ McDowell R Busby J Eastwood MC Patel PH Jackson DJ et al. Clinical remission in severe asthma with Biologic Therapy: an analysis from the UK Severe Asthma Registry. Eur Respir J. (2023) 62(6):2300819. doi: 10.1183/13993003.00819-2023
Hansen S Søndergaard M von Bülow A Bjerrum A-S Schmid J Rasmussen LM et al. Clinical response and remission in severe asthma patients treated with biologic therapies. Chest. (2024) 105(2):253–66. doi: 10.1016/j.chest.2023.10.046
Tukey JW. Some thoughts on clinical trials, especially problems of multiplicity. Science. (1977) 198:679–84. doi: 10.1126/science.333584
Muraro A Lemanske RFJ Hellings PW Akdis CA Bieber T Casale TB et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. (2016) 137:1347–58. doi: 10.1016/j.jaci.2016.03.010
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention (2023). Available online at: https://ginasthma.org/wp-content/uploads/2023/05/GINA-2023-Full-Report-2023-WMS.pdf (Accessed 26th March 2024).
FitzGerald JM Bleecker ER Menzies-Gow A Zangrilli JG Hirsch I Metcalfe P et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. (2018) 6:51–64. doi: 10.1016/S2213-2600(17)30344-2
Moermans C Brion C Bock G Graff S Gerday S Nekoee H et al. Sputum type 2 markers could predict remission in severe asthma treated with anti-IL-5. Chest. (2023) 163(6):1368–79. doi: 10.1016/j.chest.2023.01.037
Gerday S Graff S Moermans C Guissard F Paulus V Henket M et al. Super-responders to anti-IL-5/anti-IL-5R are characterised by high sputum eosinophil counts at baseline. Thorax. (2023) 78:1138–41. doi: 10.1136/thorax-2022-219781
Casale TB Luskin AT Busse W Zeiger RS Trzaskoma B Yang M et al. Omalizumab effectiveness by biomarker status in patients with asthma: evidence from PROSPERO, A prospective real-world study. J Allergy Clin Immunol Pract. (2019) 7:156–164.e1. doi: 10.1016/j.jaip.2018.04.043
Loewenthal L Menzies-Gow A. FeNO in asthma. Semin Respir Crit Care Med. (2022) 43:635–45. doi: 10.1055/s-0042-1743290
Kavati A Zhdanava M Ortiz B Lecocq J Schiffman B Pilon D et al. Retrospective study on the association of biomarkers with real-world outcomes of omalizumab-treated patients with allergic asthma. Clin Ther. (2019) 41:1956–71. doi: 10.1016/j.clinthera.2019.07.021
Solidoro P Patrucco F de Blasio F Brussino L Bellocchia M Dassetto D et al. Predictors of reversible airway obstruction with omalizumab in severe asthma: a real-life study. Ther Adv Respir Dis. (2019) 13:1753466619841274. doi: 10.1177/1753466619841274
Schleich FN Seidel L Sele J Manise M Quaedvlieg V Michils A et al. Exhaled nitric oxide thresholds associated with a sputum eosinophil count ≥3% in a cohort of unselected patients with asthma. Thorax. (2010) 65:1039–44. doi: 10.1136/thx.2009.124925
Kostikas K Minas M Papaioannou AI Papiris S Dweik RA. Exhaled nitric oxide in asthma in adults: the end is the beginning? Curr Med Chem. (2011) 18:1423–31. doi: 10.2174/092986711795328436
Zuiker RGJA Boot JD Calderon C Piantone A Petty K de Kam M et al. Sputum induction with hypertonic saline reduces fractional exhaled nitric oxide in chronic smokers and non-smokers. Respir Med. (2010) 104:917–20. doi: 10.1016/j.rmed.2010.02.006
Wahn U Martin C Freeman P Blogg M Jimenez P. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy. (2009) 64:1780–7. doi: 10.1111/j.1398-9995.2009.02119.x
Korn S Haasler I Fliedner F Becher G Strohner P Staatz A et al. Monitoring free serum IgE in severe asthma patients treated with omalizumab. Respir Med. (2012) 106:1494–500. doi: 10.1016/j.rmed.2012.07.010
Naumova V Beltyukov E Niespodziana K Errhalt P Valenta R Karaulov A et al. Cumulative IgE-levels specific for respiratory allergens as biomarker to predict efficacy of anti-IgE-based treatment of severe asthma. Front Immunol. (2022) 13:941492. doi: 10.3389/fimmu.2022.941492
Hanania NA Wenzel S Rosén K Hsieh H-J Mosesova S Choy DF et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. (2013) 187:804–11. doi: 10.1164/rccm.201208-1414OC
Wechsler ME Scelo G Larenas-Linemann DES Torres-Duque CA Maspero J Tran TN et al. Association between T2-related comorbidities and effectiveness of biologics in severe asthma. Am J Respir Crit Care Med. (2023) 209:262–72. doi: 10.1164/rccm.202305-0808OC
Heaney LG Djukanovic R Woodcock A Walker S Matthews JG Pavord ID et al. Research in progress: medical research council United Kingdom refractory asthma stratification programme (RASP-UK). Thorax. (2016) 71:187–9. doi: 10.1136/thoraxjnl-2015-207326
Silkoff PE Moore WC Sterk PJ. 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. (2019) 40:13–28. doi: 10.1016/j.ccm.2018.10.016