Activated sputum eosinophils associated with exacerbations in children on mepolizumab - 23/04/24

Doi : 10.1016/j.jaci.2024.01.031

Gabriella E. Wilson, MD ^a, James Knight, PhD ^b, Qing Liu, MD, PhD ^a, Ashish Shelar, PhD ^b, Emma Stewart, BS ^c, Xiaomei Wang, MD ^a, Xiting Yan, PhD ^a, Joshua Sanders, MS ^d, Cynthia Visness, PhD ^d, Michelle Gill, MD, PhD ^e, Rebecca Gruchalla, MD, PhD ^f, Andrew H. Liu, MD ^g, Meyer Kattan, MD ^h, Gurjit K. Khurana Hershey, MD, PhD ⁱ, Alkis Togias, MD ^j, Patrice M. Becker, MD ^j, Matthew C. Altman, MD ^k, William W. Busse, MD ^l, Daniel J. Jackson, MD ^m, Ruth R. Montgomery, PhD ^a, Geoffrey L. Chupp, MD ^a,^⁎
^a Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
^b Department of Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Conn
^c Committee on Immunology, University of Chicago, Chicago, Ill
^d Rho Federal Systems Division, Inc, Durham, NC
^e Department of Pediatric Infectious Diseases, Washington University in St Louis School of Medicine, St Louis, Mo
^f Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex
^g Department of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, Colo
^h Department of Pediatric Pulmonology, Columbia University Irving Medical Center, New York, NY
ⁱ Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati, Ohio
^j National Institute of Allergy and Infectious Diseases, Bethesda, Md
^k Benaroya Research Institute, Seattle, Wash
^l Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis
^m Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis

^∗Corresponding author: Geoffrey L. Chupp, MD, Section of Pulmonary and Critical Care, Department of Internal Medicine, Yale School of Medicine, 300 Cedar Street, New Haven, CT 06520.Section of Pulmonary and Critical CareDepartment of Internal MedicineYale School of Medicine300 Cedar StreetNew HavenCT06520

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Graphical abstract

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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.

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Key words : Interleukin-5, asthma, mass cytometry, sputum

Abbreviations used : CyTOF, NIAID, NIH, UMAP