Asthma is a widespread disease throughout the world, which hinders the performance of daily activities and reduces the quality of life of affected patients, especially in the most severe forms (Chung et al., 2014; Wilson et al., 2012). The most common and problematic symptom among asthmatic patients is exertional dyspnea, which has been hypothesized to be associated with the occurrence of dynamic hyperinflation (DH) (Haselkorn et al., 2010). DH is a well-recognized cause of physical exercise limitation among COPD patients, and is sustained by reduced alveolar attachments and consequent impaired lung elastic recoil; on the other hand, its occurrence in asthma is less investigated (Vermeulen et al., 2016), and could be attributed to different causes. In a recent study by van der Meer and colleagues (van der Meer et al., 2021), DH was shown to be associated with features of airway inflammation in moderate to severe asthmatics, and to decrease with systemic corticosteroids, thus being recognized as an important treatable trait. The same authors previously demonstrated that DH is associated with impaired physical activity in severe asthmatics (van der Meer et al., 2019).

Patients affected by severe asthma may require biologic drugs to achieve control of respiratory symptoms. Benralizumab is a monoclonal antibody directed against the IL-5 receptor, which has been proved safe and effective in reducing the number of disease exacerbations, hospitalizations and the dose of oral corticosteroids in patients affected by severe eosinophilic asthma (Nair et al., 2017; Bleecker et al., 2016; FitzGerald et al., 2016). Recent studies (Pelaia et al., 2020; Panettieri et al., 2020; Maniscalco et al., 2024) have shown a tendency to improvement in static lung volumes after treatment with benralizumab, which could further explain the clinical effects on daily activities.

In this pilot study, we sought to demonstrate that anti-IL5 receptor α monoclonal antibody is effective in reducing lung hyperinflation in severe asthmatics. For this purpose, we assessed the changes in inspiratory capacity (IC) in severe asthmatic subjects measured during the 6-min walking test (6MWT), a condition resembling daily physical activities in experimental setting.

Twelve patients (8 females and 4 males, age:57 ± 8.6 years) affected by severe eosinophilic asthma, meeting the eligibility criteria for benralizumab treatment, were recruited. All severe asthmatics enrolled in the current study were never smokers. The baseline characteristics of the enrolled patients are depicted in Table 1. No exacerbations were documented during the study period. As expected, significant improvement of dynamic volumes (Figure 1), asthma control and quality of life (Figure 2) was observed after anti IL-5R treatment (Table 2).

At T₀, pre-6MWT-IC and post-6MWT-IC were 2.40 ± 0.48 L and 1.60 ± 0.83 L, respectively (p < 0.0001). Minute ventilation (VE) at the beginning of the 6MWT was 13.88 ± 4.44 L·min⁻¹and post 6MWT was 23.77 ± 12.11 L·min⁻¹ (p < 0.0001). The distance walked was 393 ± 221 m.

At T₁, pre-6MWT-IC was 2.74 ± 1.14 L and post-6MWT-IC was 2.85 ± 1.22 L (p = NS); similarly, VE did not change (pre-6MWT vs. post-6MWT: 11.35 ± 7.34 L·min⁻¹ vs. 22.34 ± 7.06 L·min⁻¹). The average walked distance was 375 ± 186 m).

When comparing pre-6MWT-IC between T₀ and T₁, IC significantly increased after treatment period, indicating the beneficial effect of benralizumab on static hyperinflation (pre-6MWT-IC, T₀ vs. T₁: 2.40 ± 0.48 L vs 2.74 ± 1.14 L; p = 0.01). In addition, at T₁ IC did not change after exercise (p = 0.53) suggesting that DH disappeared after treatment with benralizumab (Figure 3).

No difference in terms of percutaneous oxygen saturation and meters walked in the 6MWT was observed after the treatment period.

DH is considered one of the main factors contributing to asthma symptoms and impaired daily life activity (van der Meer et al., 2019); for this reason, it is candidate to become an important treatable trait in moderate to severe asthma. In this exploratory study, we measured the IC changes to evaluate the occurrence of static and dynamic hyperinflation in experimental settings resembling daily activities. The current findings confirm the occurrence of DH in severe asthmatics, and demonstrate that a 6-month period of treatment with biologic drug is able to 1) significant increase IC at resting condition, suggesting a beneficial action on static hyperinflation, and 2) reduce the occurrence of DH, which disappeared in 10 out of 12 patients.

Static hyperinflation is a functional condition primarily caused by abnormally increased static (or quasi-static) pulmonary compliance, and is expressed by reduced IC. Although this is common in emphysema, there is evidence suggesting that static pulmonary compliance can also increase in severe asthmatics, especially during exacerbation, and return to normal condition after antinflammatory treatment (Gold et al., 1967; Gelb et al., 1998). In subjects with severe airway obstruction and high respiratory rates, with the consequent occurrence of expiratory flow-limitation, DH may occur. It is plausible to conceive that, following pharmacological treatment capable of reducing airway obstruction, IC increases because of lung deflation towards resting conditions of the respiratory system. The current findings support this phenomenon, showing an increase in IC at resting (pre-WT) conditions after treatment with biologic, which paralleled the increase in FEV₁. As mentioned above, the possibility that the biologic treatment has acted on lung compliance through unknown mechanisms cannot be excluded.

The most interesting observation is that DH disappeared after treatment with benralizumab. A real-life investigation on the effect of benralizumab on lung volumes (Pelaia et al., 2020) demonstrated clinically relevant changes in static lung volumes after 24 weeks of treatment in 22 severe asthmatics. The tendency to reduction in lung hyperinflation was also shown in a larger cohort of severe asthmatics in a phase IIIB study on benralizumab (the SOLANA study) (Panettieri et al., 2020). Maniscalco and coworkers (Maniscalco et al., 2024) conducted a retrospective observational study on the effect of biologics on lung hyperinflation, showing a tendency towards efficacy in reducing lung hyperinflation of biological agents. The novelty of our findings lies in the fact that lung volume changes were assessed with a portable spirometer during the walking test, in a condition that mimics daily common activities. In a previous study, Benfante et al. (2018) highlighted this phenomenon by studying two groups of patients (subject with severe asthma and individuals suffering from COPD) with a similar degree of obstruction. The study showed that severe asthmatics developed dynamic hyperinflation to the same extent of COPD, by means of similar reductions in IC during the WT. Another study showed that patients with history of severe asthma, in particular the “near-fatal” patients, underwent a significant decline of IC during cardiopulmonary exercise test (Rinaldo et al., 2023). These observations clearly confirm that DH occurs in the most severe forms of asthma. Recent observations demonstrated that, unlike to COPD, DH in asthmatics is strictly associated with airway inflammation and can be reduced by systemic anti-inflammatory treatment (van der Meer et al., 2021). In this context, it is possible to consider that a treatment that selectively blocks the inflammatory cascade has beneficial effects on inflamed airways. Taken together, these results suggest that systemic anti-inflammatory treatments, including monoclonal antibodies, may have the potential to positively impact on daily life activities and improve exercise capacity by decreasing DH. Available data support this assumption, by showing an effect of benralizumab on functional indices of peripheral airways (Pelaia et al., 2020; Maniscalco et al., 2024; Chan and Lipworth, 2023).

The increase of IC appears to be associated with important clinical implications in terms of exercise tolerance and perception of dyspnea, more so than the FEV1 parameter. The IC represents an indirect parameter for measuring end-expiratory lung volume, being on the other hand an extremely simple test to perform. It has been shown that the increase in IC, associated with bronchodilator therapy, significantly correlates with dyspnea at rest, with dyspnea during exercise and with physical performance and consequently with quality of life (Pretto et al., 2007). It is known that in asthmatic subjects, poor control of the symptoms of the disease, including dyspnea, is associated with a greater risk of limitation of physical activity, with a negative impact on work and daily life activities (Haselkorn et al., 2010). Carpagnagno et al. investigated the physical activity levels in patients suffering from severe asthma and treated with biologic therapy, and demonstrated that these therapies could be valuable in augmenting the physical activity level in severe asthma (Carpagnano et al., 2019). Lombardi et al. (Lombardi et al., 2023) assessed the clinical response to mepolizumab using the 6MWT, showing the potential of this test to complement the assessment of severe asthma. In this study, 6MWT showed sensitivity to change after asthma treatment and good correlations with asthma symptoms, quality of life and small airway dysfunction.

In conclusion, DH is an important target and an important treatable trait in severe asthma. The current study confirmed that severe asthmatic subjects develop DH during exercise and showed that a 6-month period of treatment with benralizumab in severe eosinophilic asthmatics is able to increase IC significantly at resting condition, suggesting a beneficial action on static hyperinflation, and to reduce significantly the occurrence of DH, impacting on daily activities and quality of life. Further studies are needed to explore these preliminary findings in a larger population of severe asthmatic subjects.