TY - JOUR
T1 - Activated sputum eosinophils associated with exacerbations in children on mepolizumab
AU - Wilson, Gabriella E.
AU - Knight, James
AU - Liu, Qing
AU - Shelar, Ashish
AU - Stewart, Emma
AU - Wang, Xiaomei
AU - Yan, Xiting
AU - Sanders, Joshua
AU - Visness, Cynthia
AU - Gill, Michelle
AU - Gruchalla, Rebecca
AU - Liu, Andrew H.
AU - Kattan, Meyer
AU - Khurana Hershey, Gurjit K.
AU - Togias, Alkis
AU - Becker, Patrice M.
AU - Altman, Matthew C.
AU - Busse, William W.
AU - Jackson, Daniel J.
AU - Montgomery, Ruth R.
AU - Chupp, Geoffrey L.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/8
Y1 - 2024/8
N2 - Background: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. Objective: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. Methods: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. Results: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). Conclusions: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.
AB - Background: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. Objective: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. Methods: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. Results: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). Conclusions: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.
KW - Interleukin-5
KW - asthma
KW - mass cytometry
KW - sputum
UR - http://www.scopus.com/inward/record.url?scp=85190974414&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2024.01.031
DO - 10.1016/j.jaci.2024.01.031
M3 - Article
C2 - 38485057
AN - SCOPUS:85190974414
SN - 0091-6749
VL - 154
SP - 297-307.e13
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -