Circulating Inflammatory Cells Persist in Severe Asthma Despite Biologic Therapy, Study Shows

A new study published in Allergy from researchers at Sweden's Karolinska Institutet reveals that biologic therapies mepolizumab and dupilumab—while clinically effective in reducing exacerbations and improving asthma control—do not fully eliminate type 2 inflammatory lymphocytes in individuals with severe asthma. Paradoxically, treatment is associated with increased frequencies of circulating type 2 innate lymphoid cells (ILC2), type 2 helper T cells (Th2), and cytotoxic T cells (Tc2), alongside phenotypic shifts that may alter their tissue homing and functional properties.

These findings suggest that persistent immune activation may continue under the surface, raising questions about the feasibility of biologic-free remission in some patients.

“We were surprised to find that blood levels of inflammatory cells increased rather than decreased,” Lorenz Wirth, doctoral student at Karolinska Institutet’s Department of Medicine in Huddinge, Sweden, said in a statement. “This could explain why inflammation of the airways often returns when the treatment is tapered or discontinued. It is important that we understand the long-term immunological effects of these drugs.”

The study addresses a critical gap in understanding how these targeted therapies influence immune cell dynamics beyond blood eosinophils. While biologics targeting interleukin (IL)-5 (eg, mepolizumab) or the IL-4 receptor alpha chain (eg, dupilumab) are now standard therapy for individuals with severe, eosinophilic, or Th2–high asthma, little is known about their impact on circulating type 2 lymphocytes—cells central to asthma pathogenesis. Given that some patients remain symptomatic despite treatment and that long-term remission is an emerging goal, researchers sought to characterize whether these cells persist or resolve with therapy.

Researchers analyzed peripheral blood samples from 40 participants with severe asthma enrolled in the longitudinal BIOCROSS study. All participants had uncontrolled asthma despite guideline-directed therapy and were treated with mepolizumab (n=33) or dupilumab (n=7). The research team collected blood samples at baseline, 4 months, and 12 months. Flow cytometry, single-cell RNA sequencing, and ex vivo stimulation assays were used to characterize type 2 lymphocyte populations and their transcriptional and functional changes over time.

FINDINGS

Clinically, both therapies led to significant improvements. Mepolizumab-treated participants showed reduced annual exacerbation rates (from 3.79 to 0.64; P <.001), decreased oral corticosteroid use, and improved Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores. Participants treated with dupilumab also improved across similar measures, though the small sample size limited statistical comparisons, authors noted.

Yasinka and colleagues were surprised that, despite these gains, both treatments were associated with increased frequencies of circulating ILC2s. Mepolizumab also increased Th2 and Tc2 cells—particularly those with a central memory phenotype. These lymphocytes exhibited reduced expression of homing receptors, suggesting the potential for decreased airway trafficking, the researchers said. Notably, CD117^low ILC2s—associated with more active Th2 inflammation—were enriched in circulation, expressing elevated levels of CD62L and KLRG1.

Transcriptional analyses further revealed that mepolizumab-treated patients had increased expression of activator protein-1 (AP-1) family genes across type 2 lymphocyte subsets; the AP-1 family mediates biologic processes including proliferation and differentiation, authors explained. Functional assays supported these findings: after 1 year of treatment, type 2 lymphocytes produced more IL-5 and IL-13 in response to stimulation, indicating preserved or even enhanced pro-inflammatory potential despite biologic therapy.

The data put the paradox in context: while biologics reduce clinical symptoms and eosinophilic inflammation, they do not eliminate, and may even enrich, a population of functionally active type 2 lymphocytes with altered trafficking patterns. The authors hypothesize that mepolizumab, in particular, may redirect these cells away from inflamed airways into circulation—a mechanism that reduces local inflammation but does not equate to immune resolution.

Wirth et al acknowledge several limitations with the study, including the small size of the dupilumab subgroup and the absence of airway tissue samples. Findings are also limited to peripheral blood, which may not fully reflect activity in lung tissue, they wrote.

The authors conclude that long-term disease control in asthma may not equate to immunologic remission. Persistent inflammatory cell populations could represent a latent risk for disease flare or may influence decisions about tapering biologics, they advised. Further research should investigate whether specific biomarkers can identify patients likely to achieve durable, treatment-free remission or whether additional strategies are needed to suppress the full spectrum of type 2 inflammation.

References

Wirth L, Weigel W, Stamper CT, et al. High-dimensional analysis of type 2 lymphocyte dynamics during mepolizumab or dupilumab treatment in severe asthma. Allergy. 2025;0:1–16 doi:10.1111/all.16633

Inflammatory cells remain in the blood after treatment of severe asthma. News release. Karolinska Institutet. June 26, 2025. Accessed July 2, 2025. https://news.ki.se/inflammatory-cells-remain-in-the-blood-after-treatment-of-severe-asthma