During the observation period, 62 patients underwent respiratory, otolaryngological, and blood examinations after three months of treatment with dupilumab, and 23 patients underwent tests after one year of treatment. During the observation period, all patients who received dupilumab had a past history of asthma or were currently receiving asthma treatment.
All the patients had not experienced any asthma attacks during the past three months and were well controlled by current asthma treatment or treatment free. Of the 62 patients who received dupilumab, 58 (93.5%) received as their first antibody therapy for asthma, and the remaining 4 (6.5%) had received antibody therapy (omalizumab=1, mepolizumab=2, benralizumab=1) immediately before dupilumab. The number of patients with mild to moderate asthma was 50, accounting for 80% of all patients, and the efficacy of dupilumab for severe cases has already been established (ref). Accordingly, we performed a series of evaluations mainly focusing on mild to moderate cases. Other characteristics and clinical background by severity are shown in Table 1.
Evaluation of clinical parameters in patients with mild to moderate asthma
Figure 1A shows the changes in type 2 inflammatory markers in mild to moderate asthma patients. FeNO decreased markedly at three months after dupilumab treatment, maintained after one year. IgE did not change at three months but showed a decreasing trend at one year (Figure1A). The peripheral blood eosinophil counts showed slight elevation without significance until one year. (Figure1A)
In mild to moderate asthma, the ACT score before treatment was generally good ( mean score: 22.9). Nonetheless, three months of dupilumab treatment significantly improved ACT score, maintained after one year. In addition, the asthma treatment steps based on the GINA strategy were also significantly downgraded at three months and after one year (Figure1B). In terms of CRSwNP-related evaluations, dupilumab dramatically improved nasal polyp score, CT grade, and odor score (VAS) at three months, which were further improved after one year (Figure1C). Furthermore, steroid therapy for CRSwNP was significantly reduced at the three months, and most patients were successfully withdrawn after one year of treatment with dupilumab (Figure1C).
Assessment of respiratory function and impedance in patients with mild to moderate asthma
With regard to respiratory function, forced expiratory volume in 1 s (FEV1), the percent predicted forced expiratory volume in 1 s (%FEV1), the percent predicted forced vital capacity (%FVC), and the FEV1/FVC ratio (FEV1%) were measured by spirometry. The pre-dupilumab value of FEV1,%FEV1, and %FVC was significantly improved at three months and maintained improvement for one year, while FEV1% did not significantly change by dupilumab treatment (Figure2A).
As for the respiratory impedance, we measured R5 and R20 as respiratory resistance (Rrs) and X5 and Fres as respiratory reactance (Xrs). Respiratory resistance (R5, R20) tended to improve, but the change was not without significance at three months (Figure2B). In addition, all respiratory impedance indices (R5, R20, X5, Fres) showed further improvement after one year, suggesting that one year of dupilumab treatment may significantly improve these indices by accumulating more patients (Figure2B).
Correlation between respiratory function test (FEV1) and respiratory impedance test
To elucidate whether FOT is as practical as spirometry in monitoring the effects of dupilumab or not, we evaluated the correlation between FEV1 and respiratory impedance indices (R5, R20, X5, and Fres) before and three months after dupilumab treatment. FEV1 and respiratory impedance correlated significantly before and three months after dupilumab treatment for mild to moderate asthma, suggesting that FOT shows a similar trend to spirometry with respect to obstructive disorders. (Figue3A). However, when we focused on individual cases, a certain number of cases were found to have discrepancies in the rate of improvement after three months of treatment by spirometry and FOT. Kanda et al. reported that FOT is useful for detecting pathophysiological changes in the respiratory system, even in asthmatic patients with normal FEV1/FVC(24). Hence, we compared the improvement rates of FEV1 and R5 after three months of dupilumab treatment in patients with FEV1/FVC above and below the mean (80.8%). In patients with above-average FEV1/FVC, the improvement rate of R5 was significantly greater than that of FEV1. Conversely, in patients with FEV1/FVC above average, the improvement rate of FEV1 tended to be larger than that of R5.
Comparison of the efficacy of dupilumab treatment according to disease severity.
In the present study, most patients were mild to moderate asthma, and the efficacy of dupilumab is mainly established in severe asthma. Although all participants, including severe cases, were clinically controlled at dupilumab administration, we compared the improvement in respiratory function, ACT, treatment step, and FeNO in response to three months of dupilumab treatment between mild to moderate and severe asthma. The spirometry indices (FEV1, %FEV1, %FVC) showed a trend of improvement in both groups, and no significant difference was observed (Figure 4). With respect to ACT score, treatment step, and FeNO, mild-moderate asthma, no significant difference was demonstrated between mild to moderate and severe asthma (Figure 4). Overall, mild-moderate and severe asthma responded similarly to three months of dupilumab treatment in the setting of clinically controlled cases.
Investigation of predictors of improvement in respiratory function
To determine the patient characteristics contributing to improved respiratory function with dupilumab in mild to moderate asthma, we compared nine factors associated with asthma and CRSwNP between patients with %FEV improvement below 3.8 L group and above 3.8 L group. Among the nine factors, pre-dose FeNO and serum IgE were significantly different between the two groups, suggesting that the higher values of FeNO and IgE can be associated with more improved respiratory function by dupilumab treatment(Table 2). In addition, a higher treatment step before starting dupilumab contributed to the improvement in %FEV1. The severity of CRS (CT score, VAS, eosinophil cell count in nasal polyps) was not significantly different between the two groups.