How <scp>FEV<sub>1</sub></scp> Improvement Induced by Anti‐<scp>IL</scp>‐5 in Severe Type‐2 Asthma Is Linked to Mucus Plugs Clearance
Authors: Alain Michils, Maxime Hackx, Lucas Mlynarski, Amaryllis Haccuria, Silvia Perez‐Bogerd, Andreï Malinovschi, Alain Van Muylem
Journal: Allergy (2024)

Biologics targeting interleukin-5 (IL-5) are widely used to treat severe eosinophilic asthma. We have recently shown that their modest effect on lung function [1], masks two opposite changes: a continuous improvement in FEV1 over time occurring in 60% of the patients or a persistent FEV1 decline in the remaining population [2]. Chronic airflow obstruction in severe asthmatics appears to be partly related to the presence of mucus plugs in the airways that are often associated with eosinophilic airway inflammation [3]. Recent data indicate that benralizumab may promote the clearance of airway mucus plugs, the presence of which is quantified by a segment-based scoring system on chest CT scan called mucus score [3], which results in improved lung function [4, 5]. The present study, approved by the local ethics committee (A2023/237), investigated, in a real-world setting, whether the improvement in FEV1 or the persistence of its deterioration in severe eosinophilic asthma patients on anti-IL-5 is related to a distinct evolution of the mucus score. Severe eosinophilic asthma patients treated with anti-IL-5 biologics (mepolizumab (n = 15), benralizumab (n = 13), reslizumab (n = 4)) were enrolled in this post hoc analysis after signing informed consent. The median follow-up time was 9 years before and 4 years after treatment start. The median number of FEV1 measurements was 12 and 7 before and after treatment start, respectively. Two groups stood out according to the evolution of FEV1 after initiation of anti-IL-5 therapy: patients who improved (FEV1 slope in %pred.year−1 ≥ 0; FEV1 responders, n = 16) and those who continued to degrade their FEV1 (FEV1 slope < 0; FEV1 non-responders, n = 16) on anti-IL5 therapy. We compared the change in mucus score between these two groups, assessed on chest CT scans performed before and after initiating anti-IL-5 with blind evaluation conducted by two independent readers. Post-start CT scans were performed at a comparable timeframe (p = 0.491) to treatment initiation in FEV1 non-responders (median 1092 days) and responders (median 1518 days). Table 1 presents the patients' characteristics. FEV1 non-responders and responders differed in smoking habits, ACQ and mucus scores, lower asthma control, and higher mucus scores observed in FEV1 responders. A multivariate logistic regression, including smoking habits, showed that only the change in mucus score was associated with FEV1 responder/non-responder status. Linear regression analysis, shown in Figure 1A, showed a significant and negative association between the mucus score variation and the slope of FEV1 after treatment initiation. Similarly, Figure 1B shows that FEV1 responders had a clear decrease in mucus score (p = 0.005) while no change in mucus score (p = 0.421) was observed in FEV1 non-responders. This study, despite limitations such as its retrospective design, the relatively limited number of patients, the heterogeneity of biologics used, … suggests that, when lung function improves in patients with severe eosinophilic asthma on anti-IL-5, this is associated with a significant reduction in mucus score. This reduction is not observed in FEV1 non-responders whose lung function continues to deteriorate. The reduction in mucus score occurs regardless of the biologic prescribed and mainly in patients with a higher mucus score, suggesting that the pathogenic mechanisms leading to mucus plug formation in severe eosinophilic asthma are likely multifactorial, less dependent on eosinophilic inflammation and therefore less sensitive to anti-IL-5 in patients with a lower mucus score. It cannot be ruled out, however, that airway eosinophilic inflammation was not totally controlled in these patients despite similar changes in blood eosinophil counts. Still, biologics with other mechanisms of action that also appear to be effective in removing mucus plugs [6] could become an alternative in patients whose mucus plugs are refractory to anti-IL-5 if the goal is also to improve lung function. Alain Michils conceived of the study, participated in its design and patient inclusion, and drafted the manuscript. Maxime Hackx and Lucas Mlynarski read the chest C.T. to establish the mucus score. Amaryllis Haccuria and Silvia Perez-Bogerd participated in patient inclusion and helped draft the manuscript. Andreï Malinovschi participated in the study's design and helped draft the manuscript. Alain Van Muylem conceived of the study, participated in its design, performed the statistical analysis, and helped draft the manuscript. All authors approved the manuscript content. The authors thank Mr. Tom O'Connell (OCPR, Brussels, Belgium) for proofreading the manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.