Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach

Eileen Wang; William Henley; Désirée Larenas-Linnemann; Lakmini Bulathsinhala; Trung N. Tran; Michael E. Wechsler; Shawn D. Aaron; Mona Al-Ahmad; Riyad Al-Lehebi; Alan Altraja; Peter Barker; Aaron Beastall; Andrey S. Belevskiy; Celine Bergeron; Leif Bjermer; Unnur S. Björnsdóttir; Sinthia Z. Bosnic-Anticevich; Arnaud Bourdin; Guy G. Brusselle; John Busby; Giorgio Walter Canonica; Victoria Carter; Kenneth R. Chapman; Nicholas Chapman; George C. Christoff; Borja G. Cosio; Richard W. Costello; James Fingleton; João A. Fonseca; Mina Gaga; Peter G. Gibson; Susanne Hansen; Liam G. Heaney; Enrico Heffler; Mark Hew; Takahiko Horiguchi; Flavia Hoyte; Richard B. Hubbard; Takashi Iwanaga; David J. Jackson; Rohit Katial; Mariko Siyue Koh; Konstantinos Kostikas; Piotr Kuna; Sverre Lehmann; Lauri Lehtimäki; Renaud Louis; Dóra Lúdvíksdóttir; Njira Lugogo; Bassam Mahboub; Neil Martin; Jorge Máspero; Andrew N. Menzies-Gow; Arjun Mohan; Ruth B. Murray; Tatsuya Nagano; Nikolaos G. Papadopoulos; Andriana I. Papaioannou; Pujan H. Patel; Luis Perez-de-Llano; Diahn Warng Perng; Matthew J. Peters; Paul E. Pfeffer; Paulo Márcio Pitrez; Roy Alton Pleasants; Todor A. Popov; Celeste M. Porsbjerg; Francesca Puggioni; Anna Quinton; Chin Kook Rhee; Mohsen Sadatsafavi; Sundeep Salvi; Giulia Scioscia; Chau Chyun Sheu; Concetta Sirena; Camille Taillé; Christian Taube; Carlos A. Torres-Duque; Ming Ju Tsai; Alf Tunsäter; Charlotte Suppli Ulrik; David B. Price

doi:10.1016/j.jaip.2025.08.021

Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach

Eileen Wang
, William Henley
, Désirée Larenas-Linnemann
, Lakmini Bulathsinhala
, Trung N. Tran
, Michael E. Wechsler
, Shawn D. Aaron
, Mona Al-Ahmad
, Riyad Al-Lehebi
, Alan Altraja
, Peter Barker
, Aaron Beastall
, Andrey S. Belevskiy
, Celine Bergeron
, Leif Bjermer
, Unnur S. Björnsdóttir
, Sinthia Z. Bosnic-Anticevich
, Arnaud Bourdin
, Guy G. Brusselle
, John Busby

Giorgio Walter Canonica, Victoria Carter, Kenneth R. Chapman, Nicholas Chapman, George C. Christoff, Borja G. Cosio, Richard W. Costello, James Fingleton, João A. Fonseca, Mina Gaga, Peter G. Gibson, Susanne Hansen, Liam G. Heaney, Enrico Heffler, Mark Hew, Takahiko Horiguchi, Flavia Hoyte, Richard B. Hubbard, Takashi Iwanaga, David J. Jackson, Rohit Katial, Mariko Siyue Koh, Konstantinos Kostikas, Piotr Kuna, Sverre Lehmann, Lauri Lehtimäki, Renaud Louis, Dóra Lúdvíksdóttir, Njira Lugogo, Bassam Mahboub, Neil Martin, Jorge Máspero, Andrew N. Menzies-Gow, Arjun Mohan, Ruth B. Murray, Tatsuya Nagano, Nikolaos G. Papadopoulos, Andriana I. Papaioannou, Pujan H. Patel, Luis Perez-de-Llano, Diahn Warng Perng, Matthew J. Peters, Paul E. Pfeffer, Paulo Márcio Pitrez, Roy Alton Pleasants, Todor A. Popov, Celeste M. Porsbjerg, Francesca Puggioni, Anna Quinton, Chin Kook Rhee, Mohsen Sadatsafavi, Sundeep Salvi, Giulia Scioscia, Chau Chyun Sheu, Concetta Sirena, Camille Taillé, Christian Taube, Carlos A. Torres-Duque, Ming Ju Tsai, Alf Tunsäter, Charlotte Suppli Ulrik, David B. Price

Department of Internal Medicine

National Jewish Health
University of Colorado Anschutz Medical Campus
Observational and Pragmatic Research Institute
Optimum Patient Care Global
University of Exeter
Fundación Clínica Médica Sur
AstraZeneca
University of Ottawa
Kuwait University
Ministry of Health, Kuwait
King Fahad Medical City
Alfaisal University
University of Tartu
Pirogov Russian National Research Medical University
Vancouver General Hospital
University of British Columbia
Lund University
Landspitali University Hospital
Macquarie University
Woolcock Institute of Medical Research
CHU Montpellier
Ghent University
Erasmus University Rotterdam
Queen's University Belfast
IRCCS Istituto Clinico Humanitas - Rozzano (Milano)
Humanitas University
University of Toronto
Exempla Saint Joseph Hospital
Bulgarian Alliance for Clinical and Translational Allergy
Hospital Universitario Son Espases
Royal College of Surgeons in Ireland
Capital & Coast District Health Board
University of Porto
Hygeia Hospital
University of Newcastle
Hunter Medical Research Institute, Australia
University of Copenhagen
Alfred Health
Monash University
Nishiyamacho
University of Nottingham
Kindai University
King's College London
Singapore General Hospital
University of Ioannina
Medical University of Łódź
University of Bergen
Tampere University
University of Liege
University of Michigan, Ann Arbor
Dubai Health Authority
Al Jalila Foundation Research Centre
University of Leicester
CIDEA Foundation
Universidad de Buenos Aires
Royal Brompton and Harefield NHS Foundation Trust
Kobe University
University of Manchester
National and Kapodistrian University of Athens
Lucus Augusti University Hospital
National Yang Ming Chiao Tung University
Veterans General Hospital-Taipei
Concord Repatriation General Hospital
Barts Health NHS Trust
Queen Mary University of London
Hospital Santa Casa de Porto Alegre
University of North Carolina at Chapel Hill
University Hospital St. Ivan Rilski
Pulmocare Research and Education Foundation
University of Foggia
Kaohsiung Medical University
SANI-Severe Asthma Network Italy
Université Paris Cité
University of Duisburg-Essen
Fundación Neumológica Colombiana
Universidad de la Sabana
University of Aberdeen

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood. Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement. Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class. Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P <. 001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti–IL-5/5 receptor (R) (but not anti-IgE or anti–IL-4Rα) for all clusters compared with cluster A. Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.

Original language	English
Pages (from-to)	3296-3315
Number of pages	20
Journal	Journal of Allergy and Clinical Immunology: In Practice
Volume	13
Issue number	12
DOIs	https://doi.org/10.1016/j.jaip.2025.08.021
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

Keywords

BEC
Benralizumab
Dupilumab
Effectiveness
FeNO
IgE
Mepolizumab
Omalizumab
Real-life
Reslizumab

Access to Document

10.1016/j.jaip.2025.08.021

Cite this

Wang, E., Henley, W., Larenas-Linnemann, D., Bulathsinhala, L., Tran, T. N., Wechsler, M. E., Aaron, S. D., Al-Ahmad, M., Al-Lehebi, R., Altraja, A., Barker, P., Beastall, A., Belevskiy, A. S., Bergeron, C., Bjermer, L., Björnsdóttir, U. S., Bosnic-Anticevich, S. Z., Bourdin, A., Brusselle, G. G., ... Price, D. B. (2025). Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach. Journal of Allergy and Clinical Immunology: In Practice, 13(12), 3296-3315. https://doi.org/10.1016/j.jaip.2025.08.021

@article{dac688b855d9480da2fea795121fef73,

title = "Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach",

abstract = "Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood. Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement. Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class. Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4\%), cluster B (20.4\%), cluster C (22.9\%), cluster D (30.3\%), and cluster E with the highest T2 involvement (10.0\%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95\% confidence interval: 0.08, 0.25]; P <. 001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti–IL-5/5 receptor (R) (but not anti-IgE or anti–IL-4Rα) for all clusters compared with cluster A. Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.",

keywords = "BEC, Benralizumab, Dupilumab, Effectiveness, FeNO, IgE, Mepolizumab, Omalizumab, Real-life, Reslizumab",

author = "Eileen Wang and William Henley and D{\'e}sir{\'e}e Larenas-Linnemann and Lakmini Bulathsinhala and Tran, \{Trung N.\} and Wechsler, \{Michael E.\} and Aaron, \{Shawn D.\} and Mona Al-Ahmad and Riyad Al-Lehebi and Alan Altraja and Peter Barker and Aaron Beastall and Belevskiy, \{Andrey S.\} and Celine Bergeron and Leif Bjermer and Bj{\"o}rnsd{\'o}ttir, \{Unnur S.\} and Bosnic-Anticevich, \{Sinthia Z.\} and Arnaud Bourdin and Brusselle, \{Guy G.\} and John Busby and Canonica, \{Giorgio Walter\} and Victoria Carter and Chapman, \{Kenneth R.\} and Nicholas Chapman and Christoff, \{George C.\} and Cosio, \{Borja G.\} and Costello, \{Richard W.\} and James Fingleton and Fonseca, \{Jo{\~a}o A.\} and Mina Gaga and Gibson, \{Peter G.\} and Susanne Hansen and Heaney, \{Liam G.\} and Enrico Heffler and Mark Hew and Takahiko Horiguchi and Flavia Hoyte and Hubbard, \{Richard B.\} and Takashi Iwanaga and Jackson, \{David J.\} and Rohit Katial and Koh, \{Mariko Siyue\} and Konstantinos Kostikas and Piotr Kuna and Sverre Lehmann and Lauri Lehtim{\"a}ki and Renaud Louis and D{\'o}ra L{\'u}dv{\'i}ksd{\'o}ttir and Njira Lugogo and Bassam Mahboub and Neil Martin and Jorge M{\'a}spero and Menzies-Gow, \{Andrew N.\} and Arjun Mohan and Murray, \{Ruth B.\} and Tatsuya Nagano and Papadopoulos, \{Nikolaos G.\} and Papaioannou, \{Andriana I.\} and Patel, \{Pujan H.\} and Luis Perez-de-Llano and Perng, \{Diahn Warng\} and Peters, \{Matthew J.\} and Pfeffer, \{Paul E.\} and Pitrez, \{Paulo M{\'a}rcio\} and Pleasants, \{Roy Alton\} and Popov, \{Todor A.\} and Porsbjerg, \{Celeste M.\} and Francesca Puggioni and Anna Quinton and Rhee, \{Chin Kook\} and Mohsen Sadatsafavi and Sundeep Salvi and Giulia Scioscia and Sheu, \{Chau Chyun\} and Concetta Sirena and Camille Taill{\'e} and Christian Taube and Torres-Duque, \{Carlos A.\} and Tsai, \{Ming Ju\} and Alf Tuns{\"a}ter and Ulrik, \{Charlotte Suppli\} and Price, \{David B.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = dec,

doi = "10.1016/j.jaip.2025.08.021",

language = "English",

volume = "13",

pages = "3296--3315",

journal = "Journal of Allergy and Clinical Immunology: In Practice",

issn = "2213-2198",

publisher = "American Academy of Allergy, Asthma and Immunology",

number = "12",

}

Wang, E, Henley, W, Larenas-Linnemann, D, Bulathsinhala, L, Tran, TN, Wechsler, ME, Aaron, SD, Al-Ahmad, M, Al-Lehebi, R, Altraja, A, Barker, P, Beastall, A, Belevskiy, AS, Bergeron, C, Bjermer, L, Björnsdóttir, US, Bosnic-Anticevich, SZ, Bourdin, A, Brusselle, GG, Busby, J, Canonica, GW, Carter, V, Chapman, KR, Chapman, N, Christoff, GC, Cosio, BG, Costello, RW, Fingleton, J, Fonseca, JA, Gaga, M, Gibson, PG, Hansen, S, Heaney, LG, Heffler, E, Hew, M, Horiguchi, T, Hoyte, F, Hubbard, RB, Iwanaga, T, Jackson, DJ, Katial, R, Koh, MS, Kostikas, K, Kuna, P, Lehmann, S, Lehtimäki, L, Louis, R, Lúdvíksdóttir, D, Lugogo, N, Mahboub, B, Martin, N, Máspero, J, Menzies-Gow, AN, Mohan, A, Murray, RB, Nagano, T, Papadopoulos, NG, Papaioannou, AI, Patel, PH, Perez-de-Llano, L, Perng, DW, Peters, MJ, Pfeffer, PE, Pitrez, PM, Pleasants, RA, Popov, TA, Porsbjerg, CM, Puggioni, F, Quinton, A, Rhee, CK, Sadatsafavi, M, Salvi, S, Scioscia, G, Sheu, CC, Sirena, C, Taillé, C, Taube, C, Torres-Duque, CA, Tsai, MJ, Tunsäter, A, Ulrik, CS & Price, DB 2025, 'Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach', Journal of Allergy and Clinical Immunology: In Practice, vol. 13, no. 12, pp. 3296-3315. https://doi.org/10.1016/j.jaip.2025.08.021

Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach. / Wang, Eileen; Henley, William; Larenas-Linnemann, Désirée et al.
In: Journal of Allergy and Clinical Immunology: In Practice, Vol. 13, No. 12, 12.2025, p. 3296-3315.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma

T2 - A Data-Driven Biomarker Clustering Approach

AU - Wang, Eileen

AU - Henley, William

AU - Larenas-Linnemann, Désirée

AU - Bulathsinhala, Lakmini

AU - Tran, Trung N.

AU - Wechsler, Michael E.

AU - Aaron, Shawn D.

AU - Al-Ahmad, Mona

AU - Al-Lehebi, Riyad

AU - Altraja, Alan

AU - Barker, Peter

AU - Beastall, Aaron

AU - Belevskiy, Andrey S.

AU - Bergeron, Celine

AU - Bjermer, Leif

AU - Björnsdóttir, Unnur S.

AU - Bosnic-Anticevich, Sinthia Z.

AU - Bourdin, Arnaud

AU - Brusselle, Guy G.

AU - Busby, John

AU - Canonica, Giorgio Walter

AU - Carter, Victoria

AU - Chapman, Kenneth R.

AU - Chapman, Nicholas

AU - Christoff, George C.

AU - Cosio, Borja G.

AU - Costello, Richard W.

AU - Fingleton, James

AU - Fonseca, João A.

AU - Gaga, Mina

AU - Gibson, Peter G.

AU - Hansen, Susanne

AU - Heaney, Liam G.

AU - Heffler, Enrico

AU - Hew, Mark

AU - Horiguchi, Takahiko

AU - Hoyte, Flavia

AU - Hubbard, Richard B.

AU - Iwanaga, Takashi

AU - Jackson, David J.

AU - Katial, Rohit

AU - Koh, Mariko Siyue

AU - Kostikas, Konstantinos

AU - Kuna, Piotr

AU - Lehmann, Sverre

AU - Lehtimäki, Lauri

AU - Louis, Renaud

AU - Lúdvíksdóttir, Dóra

AU - Lugogo, Njira

AU - Mahboub, Bassam

AU - Martin, Neil

AU - Máspero, Jorge

AU - Menzies-Gow, Andrew N.

AU - Mohan, Arjun

AU - Murray, Ruth B.

AU - Nagano, Tatsuya

AU - Papadopoulos, Nikolaos G.

AU - Papaioannou, Andriana I.

AU - Patel, Pujan H.

AU - Perez-de-Llano, Luis

AU - Perng, Diahn Warng

AU - Peters, Matthew J.

AU - Pfeffer, Paul E.

AU - Pitrez, Paulo Márcio

AU - Pleasants, Roy Alton

AU - Popov, Todor A.

AU - Porsbjerg, Celeste M.

AU - Puggioni, Francesca

AU - Quinton, Anna

AU - Rhee, Chin Kook

AU - Sadatsafavi, Mohsen

AU - Salvi, Sundeep

AU - Scioscia, Giulia

AU - Sheu, Chau Chyun

AU - Sirena, Concetta

AU - Taillé, Camille

AU - Taube, Christian

AU - Torres-Duque, Carlos A.

AU - Tsai, Ming Ju

AU - Tunsäter, Alf

AU - Ulrik, Charlotte Suppli

AU - Price, David B.

PY - 2025/12

Y1 - 2025/12

N2 - Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood. Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement. Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class. Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P <. 001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti–IL-5/5 receptor (R) (but not anti-IgE or anti–IL-4Rα) for all clusters compared with cluster A. Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.

AB - Background: Asthma with low levels of type 2 (T2) biomarkers is poorly understood. Objective: To characterize severe asthma phenotypes and compare changes in asthma outcomes from pre- to postbiologic treatment along a gradient of T2 involvement. Methods: This was a registry-based cohort study including data from 24 countries. Biomarker distribution (blood eosinophil count, fractional exhaled nitric oxide, and IgE) was quantified before biologic initiation. Clusters were identified using a 5-component Gaussian finite mixture model and phenotypically characterized. Changes in asthma and health care utilization outcomes between 1-year pre- and postbiologic initiation were compared between clusters and by biologic class. Results: Among 3675 patients, 5 biomarker clusters were identified along a gradient of T2 involvement: cluster A with the lowest T2 involvement (16.4%), cluster B (20.4%), cluster C (22.9%), cluster D (30.3%), and cluster E with the highest T2 involvement (10.0%). In multivariable analysis, biologic use was associated with improved outcomes in all clusters but tended to be better at the higher end of the T2 spectrum. For example, patients in cluster C had a significantly greater increase in forced expiratory volume in 1 second compared with cluster A (difference 0.16 L [95% confidence interval: 0.08, 0.25]; P <. 001). The odds of uncontrolled asthma were approximately 0.6 for all clusters compared with cluster A. Overall, exacerbation rates were lower, and greater improvements in lung function and asthma control were noted for anti–IL-5/5 receptor (R) (but not anti-IgE or anti–IL-4Rα) for all clusters compared with cluster A. Conclusion: T2-targeting biologics have utility in the management of asthma with low T2 involvement, but more effective therapies are needed. Further research is warranted to identify specific pathogenic pathways at the lower end of the T2 spectrum that can be effectively targeted by biologics.

KW - BEC

KW - Benralizumab

KW - Dupilumab

KW - Effectiveness

KW - FeNO

KW - IgE

KW - Mepolizumab

KW - Omalizumab

KW - Real-life

KW - Reslizumab

UR - https://www.scopus.com/pages/publications/105018976011

U2 - 10.1016/j.jaip.2025.08.021

DO - 10.1016/j.jaip.2025.08.021

M3 - Article

C2 - 40902942

AN - SCOPUS:105018976011

SN - 2213-2198

VL - 13

SP - 3296

EP - 3315

JO - Journal of Allergy and Clinical Immunology: In Practice

JF - Journal of Allergy and Clinical Immunology: In Practice

IS - 12

ER -

Response to Biologics Along a Gradient of T2 Involvement in Patients With Severe Asthma: A Data-Driven Biomarker Clustering Approach

Abstract

Bibliographical note

Keywords

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