Insights and considerations in the use of biologics for managing eosinophilic exacerbations in asthma and chronic obstructive pulmonary disease

The proportion of patients with severe asthma is relatively small among the total asthma population, but its burden is significant, including a large proportion of exacerbations and mortality (1). Thankfully, developments in biologic agents offer promising therapeutic options for severe asthma (2). As a step further in the advancement of biologic therapy for severe asthma, Ramakrishnan and colleagues recently reported their excellent work, highlighting the potential for using biologics in managing exacerbations of asthma and chronic obstructive pulmonary disease (COPD) (3). Considering that exacerbations of airway diseases are critical events that should be prevented, this study paves the way for novel therapeutic strategies beyond systemic corticosteroids.

Nevertheless, we have some questions and comments regarding the study’s design and results. The most important concern is that it is uncertain how to determine the effect of benralizumab on the exacerbation itself. In this study, the authors evaluated the primary outcome, i.e., treatment failure, at three months. This is uncommon in conventional studies evaluating the effect of steroids on acute exacerbation of asthma and COPD (4). The current outcome seems to capture overall disease stability after benralizumab use rather than the exacerbation itself.

Other concerns also exist. First, this study excluded individuals experiencing severe exacerbations that require non-invasive or invasive ventilation. Since severe exacerbations requiring high-level respiratory support have a more substantial impact on patients and healthcare systems (5), it is essential to determine whether this therapeutic approach is applicable in these critical scenarios. Although this study could not clarify this, some previous case reports have suggested that biologics could successfully manage severe exacerbations in patients with asthma (6,7). Second, intravenous (IV) administration may be more appropriate for managing acute exacerbations. While subcutaneous (SC) administration of benralizumab results in slow absorption (with an absorption half-life of approximately 3.5 days and an estimated bioavailability of 60%) (8), IV administration offers much higher bioavailability and achieves maximum drug concentration immediately at the end of infusion (9). Third, questions remain about the optimal dosing strategies for managing exacerbations of airway diseases. Notably, the benralizumab dose used in this study (100 mg) was higher than the conventional dose (30 mg). Previous studies have suggested that the initially recommended dose of biologics via the SC route could effectively manage acute exacerbations of asthma (6,10). Given the high cost of benralizumab, further studies are needed to assess whether doses lower than 100 mg or the conventional dose could effectively manage eosinophilic exacerbations. Fourth, based on the inclusion and exclusion criteria, patients with recent exacerbations and high blood eosinophil counts—who are known to benefit from benralizumab–were enrolled in the study. Thus, the results may primarily reflect outcomes consistent with previous benralizumab trials (11), demonstrating disease stabilization in patients prone to eosinophilic exacerbation, rather than indicating the drug’s efficacy in resolving the exacerbation itself. Fifth, comparing benralizumab with systemic steroids in moderate COPD exacerbations may be inappropriate, as the evidence supporting steroid use for COPD exacerbations in non-hospitalized settings has not been firmly established (12).

In addition, while a single injection might suffice for acute exacerbation management, treatment failures such as hospitalizations due to exacerbations remain a concern (3). Consequently, it is crucial to identify subgroups that could benefit from repeated or maintenance administration of biologics. For example, patients with more severe underlying conditions may benefit from maintenance treatment. Moreover, the number of COPD patients seems insufficient to draw conclusions on this topic, requiring future studies focused on this population. Lastly, given that some patients with bronchiectasis have eosinophilic inflammation, future studies should consider including those with eosinophilic exacerbations (13).

Despite these considerations, Ramakrishnan and colleagues have made a promising step forward in treating eosinophilic exacerbations of asthma and COPD. Further research is needed to validate and expand these results, particularly concerning exacerbation severity, optimal dosing of biologics, and underlying disease severity.

Acknowledgments

None.

Footnote

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2206/coif). The authors have no conflicts of interest to declare.

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