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. 2022 Sep 29;60(3):2102288.
doi: 10.1183/13993003.02288-2021. Print 2022 Sep.

T2-high asthma phenotypes across lifespan

Nicole Maison  1   2   3 , Jimmy Omony  1   3 , Sabina Illi  1   3 , Dominik Thiele  4   5 , Chrysanthi Skevaki  6   7 , Anna-Maria Dittrich  8   9 , Thomas Bahmer  5   10   11 , Klaus Friedrich Rabe  5   11 , Markus Weckmann  5   12 , Christine Happle  8   9 , Bianca Schaub  2   3 , Meike Meyer  13 , Svenja Foth  7   14 , Ernst Rietschel  13 , Harald Renz  6   7   15 , Gesine Hansen  8   9 , Matthias Volkmar Kopp  5   12   16 , Erika von Mutius  17   2   3 , Ruth Grychtol  8   9 ; ALLIANCE Study Group; ALLIANCE Study Group; Oliver Fuchs, Barbara Roesler, Nils Welchering, Naschla Kohistani-Greif, Johanna Kurz, Katja Landgraf-Rauf, Kristina Laubhahn, Claudia Liebl, Markus Ege, Alexander Hose, Esther Zeitlmann, Mira Berbig, Carola Marzi, Christina Schauberger, Ulrich Zissler, Carsten Schmidt-Weber, Isabell Ricklefs, Gesa Diekmann, Lena Liboschik, Gesche Voigt, Laila Sultansei, Gyde Nissen, Inke R König, Anne-Marie Kirsten, Frauke Pedersen, Henrik Watz, Benjamin Waschki, Christian Herzmann, Mustafa Abdo, Heike Biller, Karoline I Gaede, Xenia Bovermann, Alena Steinmetz, Berrit Liselotte Husstedt, Catharina Nitsche, Vera Veith, Marlen Szewczyk, Folke Brinkmann, Aydin Malik, Nicolaus Schwerk, Christian Dopfer, Mareike Price, Adan Chari Jirmo, Anika Habener, David S DeLuca, Svenja Gaedcke, Bin Liu, Mifflin-Rae Calveron, Stefanie Weber, Tom Schildberg, Silke van Koningsbruggen-Rietschel, Miguel Alcazar
Affiliations

T2-high asthma phenotypes across lifespan

Nicole Maison et al. Eur Respir J. .

Abstract

Rationale: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children.

Objectives: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages.

Methods: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28.

Measurements and main results: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood.

Conclusions: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.

Trial registration: ClinicalTrials.gov NCT02496468 NCT02419274.

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Conflict of interest statement

Conflict of interest: N. Maison, J. Omony, S. Illi, D. Thiele, A.M. Dittrich, C. Happle, M. Meyer, S. Foth and R. Grychtol have nothing to disclose. C. Skevaki reports grants and personal fees from Hycor Biomedical, Bencard Allergie, Thermo Fisher Scientific as well as grants from Mead Johnson Nutrition (MJN), Universities Giessen and Marburg Lung Centre, the German Centre for Lung Research (DZL), University Hospital Giessen and Marburg, Deutsche Forschungsgemeinschaft (DFG). T. Bahmer reports grants from the Federal Ministry for Education and Research (BMBF) for the German Center for Lung Research (DZL) and personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Roche and Chiesi. M. Weckmann reports grants from Federal Ministry for Education and Research (BMBF), University of Luebeck and German Academic Exchange Service. B. Schaub reports grants from DFG, BMBF, the EU as well from GlaxoSmithKline, Sanofi and Novartis. H. Renz reports grants from German Center for Lung Disease (DZL) and Universities Giessen Marburg Lung Center. M.V. Kopp reports grants and personal fees from Allergopharma GmbH and Vertex GmbH; additional, personal fees from Sanofi GmbH, Infectopharm GmbH and Leti GmbH. E. Rietschel reports personal lecture payments for Nutricia Milupa GmbH and Novartis Pharma, and honoraria for participation in advisory boards for MICE-Mylan, Novartis Pharma GmbH and Boehringer Ingelheim GmbH. K.F. Rabe recieved personal payments or honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie and Roche; K.F. Rabe also discloses participation on data safety monitoring boards/advisory boards for AstraZeneca and Sanofi Regeneron, and leadership or fiduciary role in the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society (ATS). G. Hansen reports grants from German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG) as well as personal fees from Sanofi GmbH, MedUpdate, and Abbvie. E. von Mutius reports grants from the German Center for Lung Research (DZL) as well as royalties/licenses held by Elsevier GmbH, Gerog Thieme Verlag, Springer Verlag GmbH, Elsevier Ltd; furthermore, consultation fees were received from the Chinese University of Hong Kong, European Commission, HiPP GmbH and AstraZeneca; E. von Mutius also received payments and/or support for meetings/travel from the Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd, Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), University Utrecht, Salzburg, Colorado and Imperial College London, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology, Klinkum Rechts der Isar, Paul-Martini-Stiftung; further support for meetings/travel was granted by Verein zur Förderung der Pneumologie am Krankenhaus Groshansdorf, Pneumologie Development Mondial Congress & Events GmbH, American Academy of Allergy, Asthma & Immunology, Margaux Orange, Volkswagen Stiftung, Österreichische Gesellschaft für Allergologie & Immunologie, OM Pharma SA, Hanson Wade Ltd, iKOMM GmbH, DSI Dansk Bornestma Center, American Thoracic Society, HiPP GmbH; E. von Mutius has patent EP2361632, EP1411977, EP1637147 and EP 1964570 (licensed to Protectimmun), furthermore patent LU101064 is pending; E. von Mutius participates in the following data monitoring or advisory boards: EXPANSE, BEAMS External Scientific Advisory Board, Journal of Allergy and Clinical Immunology: in Practice, Children's Respiratory and Environmental Workgroup (CREW), International Scientific & Societal Advisory Board of Utrecht Life Sciences, External Review Panel of the Faculty of Veterinary Science (University of Utrecht), Gottfried Wilhelm Leibniz Programme, Asthma UK for Applied Research, Advisory Board of The Lancet Respiratory Medicine, CHILD (Canadian Healthy Infant Longitudinal Development Study).

Figures

FIGURE 1
FIGURE 1
Distribution of blood eosinophils counts of healthy children and adults. Distribution of blood eosinophil levels among a) healthy children (n=275) and b) healthy adults (n=64) in the All Age Asthma Cohort (ALLIANCE) cohort. Lines indicate median, 90th percentile and literature-based cut-offs (150 cells·µL−1 and 300 cells·µL−1).
FIGURE 2
FIGURE 2
Asthma outcome of children included as preschool wheezers. Clinical outcomes of children included with preschool wheeze were assessed at the first visit aged ≥6 years and classified as remission, asthma, intermittent asthma or unclear status. Mean±sd age was 6.7±0.65 years. Children were grouped according to T2 phenotypes at baseline.
FIGURE 3
FIGURE 3
Prevalence of type 2 (T2) asthma phenotypes across all age groups. T2 phenotypes in a) children with preschool wheeze (aged <6 years) or asthma (aged ≥6 years), and b) adults with asthma. Phenotypes were defined as atopy-only (children: blood eosinophils (b-Eos) <470 cells·µL−1, adults: b-Eos <360 cells·µL−1, any specific immunoglobulin E (sIgE) ≥0.7 kU·L−1); Eos-only (children: b-Eos ≥470 cells·µL−1, adults: b-Eos ≥360 cells·µL−1, all sIgE <0.7 kU·L−1); T2-high (children: b-Eos ≥470 cells·µL−1, adults: b-Eos ≥360 cells·µL−1, any sIgE ≥0.7 kU·L−1); and T2-low (children: b-Eos <470 cells·µL−1, adults: b-Eos <360 cells·µL−1, all sIgE <0.7 kU·L−1).
FIGURE 4
FIGURE 4
Longitudinal stability of type 2 (T2) asthma phenotypes. Asthma phenotypes are shown at baseline and at two follow-ups after 12 (t12) and 24 months (t24) in children. Adults had one follow-up after 12 months (t12). Clustering was done according to baseline phenotype. a) Children with preschool wheeze (aged <6 years), n=85; b) children with asthma (aged ≥6 years), n=147; c) adults with asthma (aged 18–45 years), n=46; d) adults with asthma (aged ≥45 years), n=134. Eos: eosinophils.
FIGURE 5
FIGURE 5
Multivariable logistic regression models: association between atopy and blood eosinophils with preschool wheeze and asthma. Contribution of atopy and blood eosinophils is shown for risk of preschool wheeze and asthma after adjustment for confounders. a) Children with wheeze versus healthy children (aged <6 years); b) children with asthma versus healthy children (aged ≥6 years); c) adult asthma patients versus healthy adults (aged ≥18 to <45 years); and d) adult asthma patients versus healthy adults (aged ≥45 years). Atopy was defined as at least one allergen with specific immunoglobulin E ≥0.7 kU·L−1. aOR: adjusted odds ratio.
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