Activated sputum eosinophils associated with exacerbations in children on mepolizumab

Gabriella E Wilson; James Knight; Qing Liu; Ashish Shelar; Emma Stewart; Xiaomei Wang; Xiting Yan; Joshua Sanders; Cynthia Visness; Michelle Gill; Rebecca Gruchalla; Andrew H Liu; Meyer Kattan; Gurjit K Khurana Hershey; Alkis Togias; Patrice M Becker; Matthew C Altman; William W Busse; Daniel J Jackson; Ruth R Montgomery; Geoffrey L Chupp

doi:10.1016/j.jaci.2024.01.031

Activated sputum eosinophils associated with exacerbations in children on mepolizumab

J Allergy Clin Immunol. 2024 Mar 12:S0091-6749(24)00241-0. doi: 10.1016/j.jaci.2024.01.031. Online ahead of print.

Authors

Gabriella E Wilson¹, James Knight², Qing Liu¹, Ashish Shelar², Emma Stewart³, Xiaomei Wang¹, Xiting Yan¹, Joshua Sanders⁴, Cynthia Visness⁴, Michelle Gill⁵, Rebecca Gruchalla⁶, Andrew H Liu⁷, Meyer Kattan⁸, Gurjit K Khurana Hershey⁹, Alkis Togias¹⁰, Patrice M Becker¹⁰, Matthew C Altman¹¹, William W Busse¹², Daniel J Jackson¹³, Ruth R Montgomery¹, Geoffrey L Chupp¹⁴

Affiliations

¹ Department of Internal Medicine, Yale School of Medicine, New Haven, Conn.
² Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Conn.
³ Committee on Immunology, University of Chicago, Chicago, Ill.
⁴ Rho Federal Systems Division, Inc, Durham, NC.
⁵ Department of Pediatric Infectious Diseases, Washington University in St Louis School of Medicine, St Louis, Mo.
⁶ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex.
⁷ Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colo.
⁸ Department of Pediatric Pulmonology, Columbia University Irving Medical Center, New York, NY.
⁹ Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio.
¹⁰ National Institute of Allergy and Infectious Diseases, Bethesda, Md.
¹¹ Benaroya Research Institute, Seattle, Wash.
¹² Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹³ Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
¹⁴ Department of Internal Medicine, Yale School of Medicine, New Haven, Conn. Electronic address: Geoffrey.chupp@yale.edu.

PMID: 38485057
DOI: 10.1016/j.jaci.2024.01.031

Abstract

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. CD62L^int and CD62L^hi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62L^int and CD62L^hi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62L^int, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62L^hi, 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, CD62L^int and CD62L^hi 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.

Keywords: Interleukin-5; asthma; mass cytometry; sputum.

Abstract

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