Dynamic Changes in Type 2 Inflammatory Markers Correlated with Clinical Outcomes in T2-High Severe Asthma Treated with Omalizumab and Mepolizumab

Dynamic Changes in Type 2 Inflammatory Markers Correlated with Clinical Outcomes in T2-High Severe Asthma Treated with Omalizumab and Mepolizumab | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 17 January 2025 V1 Latest version Share on Dynamic Changes in Type 2 Inflammatory Markers Correlated with Clinical Outcomes in T2-High Severe Asthma Treated with Omalizumab and Mepolizumab Authors : Chia-Wei Chang , Shin-Wei Wu , Shin-En Tang , Chen-Liang Tsai , and Chia-Hsin Liu 0000-0002-8998-4098 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173711887.76033374/v1 260 views 106 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: This study explores the impact of omalizumab and mepolizumab on the dynamic changes in type 2 (T2) markers (blood eosinophils, serum total IgE) and their correlation with clinical outcomes in T2-high severe asthma. Methods: Ninety patients with T2-high severe asthma treated with omalizumab (n=50) or mepolizumab (n=40) were followed prospectively, with asthma control test (ACT) scores, forced expiratory volume in 1 second (FEV1), acute exacerbations (AE), and steroid use assessed at baseline, 6, and 12 months. Changes in T2 markers were analyzed for their correlations with improvements in clinical outcomes. Results: Both treatments significantly improved ACT scores and FEV1 at 6 and 12 months. AE and steroid use also significantly decreased. Blood eosinophil counts significantly reduced in both treatment groups, while total IgE levels increased with omalizumab but showed a non-significant decrease with mepolizumab at 6 and 12 months. Baseline blood eosinophils and total IgE levels demonstrated a significant moderate correlation in both treatment groups (omalizumab: r = 0.31, p = 0.0403; mepolizumab: r = 0.44, p = 0.0182). In the omalizumab group, higher baseline blood eosinophils were associated with greater FEV1 improvement ( r = 0.65, p = 0.001; r = 0.53, p = 0.012), while in the mepolizumab group, total IgE level reductions correlated with improved FEV1( r = -0.77, p = 0.042; r = -0.66, p = 0.02) at 6 and 12 months. Conclusion: Omalizumab and mepolizumab improved clinical outcomes and uniquely influenced T2 marker dynamics in T2-high severe asthma, with baseline blood eosinophils and total IgE level reductions predicting FEV1 improvements, respectively. Dynamic Changes in Type 2 Inflammatory Markers Correlated with Clinical Outcomes in T2-High Severe Asthma Treated with Omalizumab and Mepolizumab Chia-Wei Chang 1 , Shin-Wei Wu 1 , Shin-En Tang 1,2,3 , Chen-Liang Tsai 1 , Chia-Hsin Liu 1 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 2 Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan 3 Department of Medicine, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan Corresponding authors: Chia-Hsin Liu, MD, PhD Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Gung Road, Nei-Hu Dist. 114, Taipei, Taiwan. Email: [email protected] Telephone: +886-87923311 ext. 16881 Running title: T2 Marker Dynamics in Severe Asthma. Abstract Background: This study explores the impact of omalizumab and mepolizumab on the dynamic changes in type 2 (T2) markers (blood eosinophils, serum total IgE) and their correlation with clinical outcomes in T2-high severe asthma. Methods: Ninety patients with T2-high severe asthma treated with omalizumab (n=50) or mepolizumab (n=40) were followed prospectively, with asthma control test (ACT) scores, forced expiratory volume in 1 second (FEV1), acute exacerbations (AE), and steroid use assessed at baseline, 6, and 12 months. Changes in T2 markers were analyzed for their correlations with improvements in clinical outcomes. Results: Both treatments significantly improved ACT scores and FEV1 at 6 and 12 months. AE and steroid use also significantly decreased. Blood eosinophil counts significantly reduced in both treatment groups, while total IgE levels increased with omalizumab but showed a non-significant decrease with mepolizumab at 6 and 12 months. Baseline blood eosinophils and total IgE levels demonstrated a significant moderate correlation in both treatment groups (omalizumab: r = 0.31, p = 0.0403; mepolizumab: r = 0.44, p = 0.0182). In the omalizumab group, higher baseline blood eosinophils were associated with greater FEV1 improvement ( r = 0.65, p = 0.001; r = 0.53, p = 0.012), while in the mepolizumab group, total IgE level reductions correlated with improved FEV1( r = -0.77, p = 0.042; r = -0.66, p = 0.02) at 6 and 12 months. Conclusion: Omalizumab and mepolizumab improved clinical outcomes and uniquely influenced T2 marker dynamics in T2-high severe asthma, with baseline blood eosinophils and total IgE level reductions predicting FEV1 improvements, respectively. KEYWORDS T2-high severe asthma, omalizumab, mepolizumab, eosinophils, IgE, FEV1 1 BACKGROUND Severe asthma, which affects 5% to 10% of asthma patients, remains associated with substantial morbidity, mortality, and economic burden, even with the maximal use of inhaled corticosteroids and other controller medications. 1-3 Type 2 (T2) inflammation, a hallmark of T2-high severe asthma, is characterized by elevated blood eosinophils, increased fractional exhaled nitric oxide (FeNO), and often accompanied by atopy and elevated serum total IgE levels, which are commonly used as biomarkers to assess disease severity and treatment response. 4, 5 The most common biologic therapies targeting different aspects of T2 inflammation, such as omalizumab (IgE) and mepolizumab (IL-5), have proven effective in improving asthma control and lung function, reducing exacerbations, and minimizing systemic corticosteroid use, particularly in patients with T2-high severe asthma. 6, 7 Increased peripheral blood eosinophil counts are associated with increased airway inflammation, poor asthma control, and a higher risk of severe exacerbations. 8, 9 Furthermore, biologics such as omalizumab and mepolizumab have shown that higher baseline blood eosinophil counts are associated with better treatment response. 7 For omalizumab, post hoc analyses of previous clinical trials demonstrated a greater reduction in exacerbations compared to placebo in severe asthma patients with baseline blood eosinophil levels of ≥260/μL or ≥300/μL. 10, 11 Nevertheless, in two large observational studies, exacerbations were reduced regardless of blood eosinophil levels. 12, 13 Similarly, for mepolizumab, a post hoc analysis of two clinical trials revealed clinically significant reductions in exacerbation frequency in severe asthma patients with baseline eosinophil counts of ≥150/μL. Elevated serum total IgE levels, driven by IL-4-induced immunoglobulin class switching in B cells, are associated with allergic asthma and may contribute to reduced lung function. 14, 15 While baseline serum total IgE levels are used as an inclusion criterion and dosing factor for omalizumab, they are not reliable prognostic markers for assessing asthma exacerbation risk or predictive indicators for treatment response when selecting an appropriate biologic therapy. 16 Omalizumab and mepolizumab both reduce blood eosinophil counts 17, 18 , but only omalizumab increases serum IgE levels through the formation of omalizumab: IgE complexes, whereas mepolizumab has no effect on serum IgE levels. 18, 19 While both biologics targeting distinct T2 pathways have demonstrated efficacy in severe asthma, their effects on dynamic changes in T2 markers and their association with clinical improvements remain unclear. This study aims to evaluate the longitudinal effects of omalizumab and mepolizumab on blood eosinophil levels and serum total IgE, and to investigate their associations with changes in asthma control, lung function, exacerbation rates, and steroid use over 12 months in patients with T2-high severe asthma. We hypothesize that blood eosinophils and serum total IgE levels exhibit distinct changes in response to these biologics, which are associated with specific clinical improvements in patients with T2-high severe asthma. 2 METHODS 2.1 Setting and participants All adult patients who started treatment with either omalizumab or mepolizumab between January 2011 and April 2024 at a tertiary hospital asthma clinic (Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan) were included in the study. These patients received biological therapies through an application to the National Health Insurance (NHI). In Taiwan, the reimbursement for omalizumab and mepolizumab under the NHI system involves a stringent application process with specific eligibility criteria for each medication. For omalizumab, applications must be made by a pulmonologist or allergist, with patients meeting criteria including total serum IgE levels between 30-1300 IU/mL, uncontrolled asthma despite using daily inhaled corticosteroids (≥800 mcg beclomethasone dipropionate or equivalent) combined with other treatments, and documented asthma or positive bronchodilator response (FEV1 reversibility rate exceeding 12% with an increase of at least 200 mL) or systemic corticosteroid-induced FEV1 improvement (≥20% increase in FEV1). For mepolizumab, patients must have severe eosinophilic asthma (blood eosinophil count ≥300 cells/µL within the past year), uncontrolled asthma despite Step 5 therapy (as per GINA guidelines), continued use of oral corticosteroids (≥5 mg prednisolone per day or equivalent) over the past 6 months, and at least two exacerbations in the past year, one of which required emergency care. Treatment continuation, assessed every 6 months, requires objective improvements in FEV1, ACT scores, exacerbation frequency, or oral steroid use. Monoclonal antibody injections were administered by nursing staff, with prescriptions tracked through hospital pharmacies, and inhaler techniques reviewed regularly. 2.2 Assessments All patients underwent formal assessments at baseline, 6 months, and 12 months, with data recorded at the time of evaluation. Assessment interviews were conducted by trained respiratory medical and nursing staff. Data collected included demographics, asthma medication usage, ACT scores, lung function, exacerbation history, blood eosinophil counts, serum total IgE levels, and maintenance oral steroid dose. Lung function tests were performed in accredited respiratory laboratories by trained scientific staff, using instruments calibrated on the day of testing. The predicted data set was sourced from the Global Lung Initiative. 20 All tests were conducted with bronchodilators withheld on the day of testing, in accordance with European Respiratory Society and American Thoracic Society standards. 21 An exacerbation was defined as a worsening of asthma symptoms, such as increased shortness of breath, wheezing, chest tightness, or cough, and the need for a change in treatment, such as an increased need for reliever medications, systemic corticosteroids, or emergency medical intervention. 22 The frequency was based on the patient’s report during the interview. 2.3 Statistical analysis Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as frequencies and percentages (%). Descriptive statistics summarized demographics and clinical characteristics. Repeated measures ANOVA was used to compare continuous outcomes at baseline, 6, and 12 months, with post-hoc tests for multiple comparisons ( * p ≤ 0.05, ** p ≤ 0.01). Pearson correlation coefficients were calculated to assess relationships between blood eosinophil counts and IgE levels, with correlation coefficients ( r ) and corresponding p -values reported. A correlation heatmap visualized relationships between clinical variables and changes in T2 markers for patients treated with omalizumab and mepolizumab, using significance thresholds for meaningful correlations. Analyses were conducted using SPSS (version 29). 3 RESULTS 3.1 Study population A total of 101 patients were treated with either omalizumab or mepolizumab during the study period. Of these, 4 patients switched from one agent to the other. Therefore, only the first treatment received was included, in order to eliminate any carryover effect from one treatment to the next, thus reducing the study population to 97 patients (Figure 1). Of these 97 patients, 7 had discontinued therapy before the first outcome assessment at 6 months. These patients were excluded from the outcome analyses given the absence of outcome data, leaving a final population of 90 patients (50 omalizumab, 40 mepolizumab; Figure 1). The baseline characteristics of the study population, as shown in Table 1, revealed comparable demographics between the omalizumab (n = 50) and mepolizumab (n = 40) groups. The mean age was similar between the two groups, with 54.8 years in the omalizumab group and 57.0 years in the mepolizumab group. The gender distribution was also similar, with 42.5% of the omalizumab group and 35.1% of the mepolizumab group being male. Both groups demonstrated comparable body mass index (BMI), with averages of 26.0 kg/m² in the omalizumab group and 25.5 kg/m² in the mepolizumab group. There was a significant difference in smoking status, with a higher percentage of current smokers in the mepolizumab group (14%) compared to the omalizumab group (5%). However, the majority of participants in both groups were never smokers (65% in the omalizumab group and 63% in the mepolizumab group). Lung function measurements, including pre-bronchodilator forced expiratory volume in one second (FEV1) and percentage of predicted FEV1, showed no significant differences between the groups. Both groups also displayed similar scores on the Asthma Control Test (ACT). Both groups had elevated blood eosinophil counts, though a significant difference was found, with the mepolizumab group showing higher counts (757.8 ± 684.1) compared to the omalizumab group (268.2 ± 395.6), indicating T2-high severe asthma in both treatment groups. Though total blood IgE levels were higher in the mepolizumab group (620.5 ± 603.2) than the omalizumab group (458.62 ± 348.1), this difference was not statistically significant. Asthma exacerbation frequency in the six months before treatment initiation was comparable between the groups, as was the use of inhalers, with most patients utilizing triple therapy. Although oral corticosteroid use was slightly higher in the mepolizumab group, this difference was not statistically significant. 3.2 Clinical Outcomes of Omalizumab and Mepolizumab Treatment 3.2.1 Asthma Control Test Scores Both omalizumab and mepolizumab led to significant improvements in ACT scores over time. Patients treated with omalizumab showed an increase in ACT score changes from baseline to 6 months (5.71 ± 1.02, p < 0.0001) and continued improvement at 12 months (4.38 ± 1.26, p = 0.004) (Figure 2A). Similarly, mepolizumab treatment resulted in significant improvements in ACT scores, with increases from baseline observed at both 6 months (5.30 ± 0.74, p < 0.0001) and 12 months (6.83 ± 0.92, p < 0.0001) (Figure 2B). 3.2.2 FEV1 Lung function, measured by FEV1 (L), improved in both treatment groups. Omalizumab treatment led to significant increases at both 6 months (0.14 ± 0.05, p = 0.030) and 12 months (0.17 ± 0.06, p = 0.025) compared to the baseline (Figure 2C). Similarly, patients receiving mepolizumab demonstrated consistent improvement in FEV1, with significant increases from baseline at both 6 months (0.24 ± 0.08, p = 0.011) and 12 months (0.20 ± 0.08, p = 0.044) (Figure 2D). 3.2.3 Asthma Exacerbations Omalizumab and mepolizumab significantly reduced the frequency of asthma exacerbations. In the omalizumab group, a marked reduction in exacerbations was observed at 6 months (1.98 ± 0.23, p < 0.0001) and continued through 12 months (1.77 ± 0.27, p < 0.0001) compared to the baseline (Figure 2E). Mepolizumab treatment also resulted in a substantial decrease, with significant reductions from baseline at both 6 months (1.87 ± 0.22, p < 0.0001) and 12 months (1.53 ± 0.26, p < 0.0001) (Figure 2F). 3.2.4 Maintenance Oral Corticosteroid Dose The required steroid dose was significantly reduced in both the omalizumab and mepolizumab treatment groups. In the omalizumab group, the mean steroid dose changes from baseline showed a significant decrease at both 6 months (4.74 ± 1.15, p = 0.0004) and 12 months (3.95 ± 0.85, p = 0.0001) (Figure 2G). Similarly, patients receiving mepolizumab experienced a significant reduction in the mean steroid dose, with notable decreases from baseline at both 6 months (6.13 ± 1.20, p < 0.0001) and 12 months (7.13 ± 1.25, p < 0.0001) (Figure 2H). 3. Changes in Type 2 Inflammatory Markers with Omalizumab and Mepolizumab Treatment 3.3.1 Blood Eosinophil Counts Treatment with both omalizumab and mepolizumab resulted in significant reductions in blood eosinophil counts over time. In the omalizumab group, blood eosinophil counts significantly decreased from baseline (268.2 ± 395.6) to 6 months (163.4 ± 147.0, p = 0.039) and continued to decrease through 12 months (210.5 ± 175.1, p = 0.0002) (Figure 3A). Similarly, in the mepolizumab group, a significant reduction in blood eosinophil counts was observed from baseline (757.8 ± 684.1) to 6 months (81.1 ± 87.4, p < 0.0001) and sustained through 12 months (108.2 ± 159.9, p < 0.0001) (Figure 3B). 3.3.2 Total IgE Levels Omalizumab treatment significantly affected total IgE levels, with a notable increase from baseline (458.62 ± 348.1) to 6 months (631.8 ± 401.6, p = 0.0004) and 12 months (566.9 ± 380.4, p = 0.036) (Figure C). In contrast, mepolizumab treatment showed a slight decrease in total IgE levels over time, but this change did not reach statistical significance (Figure D). 3.3.3 Correlation Between Blood Eosinophil Counts and Serum Total IgE Levels A positive correlation was found between blood eosinophil counts and total IgE levels in patients treated with omalizumab, with a correlation coefficient of 0.31 ( p = 0.0403) (Figure E). Similarly, in patients treated with mepolizumab, a significant positive correlation was observed, with a correlation coefficient of 0.44 ( p = 0.0182) (Figure F). 3.4 Correlation Between Changes in Type 2 Inflammatory Markers and Improvements in Clinical Outcomes For omalizumab treatment, baseline blood eosinophil counts showed a significant positive correlation with FEV1 change from baseline at 6 months ( r = 0.649, p = 0.001) and at 12 months ( r = 0.528, p = 0.012) (Figure 4A). These results suggest that higher baseline blood eosinophil counts are associated with greater improvements in lung function over time. However, no significant correlations were found between baseline blood eosinophil counts and changes in ACT scores, AEs, or steroid dose at either 6 or 12 months (Figure 4A). Similarly, changes in blood eosinophil levels from baseline at 6 and 12 months did not show significant correlations with clinical outcomes. In omalizumab-treated patients, no significant correlations were found between total IgE levels—either pre-treatment or changes in total IgE levels—and clinical outcomes. For mepolizumab treatment, there was no significant correlation between baseline and changes in blood eosinophil counts with clinical outcomes. Interestingly, although pre-treatment total IgE levels did not show a significant correlation with clinical outcomes, total IgE level changes at both 6 and 12 months were significantly negatively correlated with FEV1 change at 6 and 12 months, indicating that greater reductions in IgE levels were associated with greater improvements in lung function (6 months: r = -0.77, p = 0.042; 12 months: r = -0.673, p = 0.037). These findings highlight the role of baseline blood eosinophil levels and changes in total IgE levels in predicting lung function improvements in patients with T2-high severe asthma treated with omalizumab and mepolizumab, respectively, while other clinical outcomes showed no significant associations with these biomarkers. We further analyzed the changes in FEV1 at 6 and 12 months, along with changes in other clinical outcomes, but no significant associations were found except significant positive associations between FEV1 improvements at 6 and 12 months ( r = 0.85, p < 0.01) (Figure S1A and S1B). These findings suggest distinct mechanisms underlying the changes in T2 markers and lung function improvements. 4 DISCUSSION Our longitudinal study demonstrates that omalizumab and mepolizumab significantly improve asthma control and lung function, reduce exacerbations, and decrease maintenance oral corticosteroid use at 6 and 12 months in T2-high severe asthma. Furthermore, the two biologics differentially influence T2 markers, with both reducing blood eosinophil counts, while only omalizumab increases serum total IgE levels at 6 and 12 months. Baseline blood eosinophil counts moderately correlated with pre-treatment serum total IgE levels. Notably, baseline blood eosinophil and total IgE level reductions were significantly correlated with FEV1 improvements at 6 months and 12 months for omalizumab and mepolizumab, respectively. Most studies have evaluated the efficacy of either omalizumab or mepolizumab individually, without simultaneously evaluating their effects on changes in T2 markers and improvements in clinical outcomes across different time points. A retrospective study of patients with atopic and eosinophilic overlap severe asthma treated with omalizumab or mepolizumab for at least 16 weeks demonstrated that both biologics improved ACT scores, reduced asthma attacks, enhanced FEV1, and lowered peripheral blood eosinophil levels. 23 Although these findings align with our study, they do not evaluate the long-term efficacy of biologics over a one-year period. Furthermore, the dynamic changes in total IgE levels with both biologics were not explored. Our study demonstrated that both biologics achieved significant clinical efficacy by 6 months, with these benefits sustained through 12 months, suggesting that treatment effects can be attained within 6 months and maintained over a 12-month period. Moreover, the dynamic changes in T2 markers showed a similar pattern, except for the lack of significant change in total IgE levels with mepolizumab treatment. Another study assessed the efficacy of mepolizumab, omalizumab, and benralizumab in terms of symptom control (Asthma Control Questionnaire-5 [ACQ-5]), lung function (FEV1 and Peak Expiratory Flow Rate [PEFR]), and exacerbations at 4–6 months and 1 year in patients with severe asthma 18 . While significant improvements in ACQ-5 scores were observed with all biologics at both time points, the percentage increase in FEV1 and PEFR from baseline, as well as the reduction in exacerbations, was not statistically significant. The discrepancy between these findings and ours may be partly explained by the higher BMI (30.2 ± 5.0 kg/m²) reported in that study, as obesity is known to reduce the efficacy of biologics by increasing systemic inflammation, altering T2 pathways, and impairing pharmacological effectiveness. 24 Despite the conceptual value of measuring biomarkers after the initiation of biological therapy, their role in monitoring treatment responses in clinical practice remains unclear. 16 A retrospective analysis of five trials in moderate-to-severe allergic asthma found that patients receiving omalizumab had greater reductions in peripheral blood eosinophil counts and greater improvements in clinical outcomes, including fewer exacerbations requiring oral steroids, increased FEV1, and positive Global Evaluation of Treatment Effectiveness ratings, compared to placebo. 25 Furthermore, weak associations, as measured by Pearson and Spearman correlation coefficients, were observed between changes from baseline in blood eosinophil counts and various clinical variables, with the data not presented in the study. In our study, changes in peripheral blood eosinophil counts did not significantly correlate with clinical outcomes, except that baseline blood eosinophil counts were moderately correlated with FEV1 improvement ( r = 0.65 at 6 months and r = 0.53 at 12 months). Additionally, pre-treatment total IgE levels and changes in blood IgE levels after omalizumab treatment did not correlate with clinical outcomes. A retrospective, multicenter study demonstrated that in patients treated with benralizumab, the reduction in blood total IgE levels showed a weak but significant correlation with improvement in asthma control, which was not observed with mepolizumab. 18 In contrast, our study showed that while blood IgE levels did not change after mepolizumab treatment, its reduction was moderately associated with FEV1 improvement ( r = -0.77 at 6 months and r = -0.65 at 12 months). Furthermore, baseline peripheral blood eosinophils and their changes after mepolizumab treatment did not correlate with clinical outcomes. The discrepancies between our findings and previous studies likely arise from differences in study design, patient populations, and analytical approaches. Earlier studies predominantly relied on retrospective analyses or shorter follow-up periods, focusing on single absolute reductions or baseline values of blood eosinophils or total IgE levels, while overlooking dynamic changes over time and their simultaneous correlations with clinical improvements. 18, 25 These studies included broader populations, such as moderate-to-severe allergic asthma patients or pooled randomized trials, which may have attenuated correlations between T2 marker dynamics and clinical outcomes. In contrast, our prospective study specifically targeted patients with T2-high severe asthma and included longitudinal follow-up at 6 and 12 months. This approach allowed us to capture the temporal dynamics of biomarker changes and their associations with clinical outcomes more comprehensively. Moreover, we evaluated multiple clinical parameters concurrently, including asthma control, lung function, exacerbation rates, and maintenance oral steroid use, providing a comprehensive understanding of changes in T2 markers and their associations with specific clinical improvements. Our study revealed unique findings, including the correlation between baseline blood eosinophils and FEV1 improvement in omalizumab-treated patients and the association of total IgE level reductions with FEV1 improvement in mepolizumab-treated patients, suggesting distinct mechanisms of efficacy. Interestingly, despite omalizumab targeting IgE and mepolizumab targeting eosinophils, the results showed unexpected patterns: FEV1 improvement was associated with blood eosinophils in the omalizumab group and with blood IgE level reductions in the mepolizumab group. Additionally, we observed that changes in FEV1 at 6 and 12 months were not associated with improvements in other clinical outcomes in either the omalizumab or mepolizumab groups. These findings demonstrate biomarker-specific effects driving lung function improvements and underscore the need for further research to elucidate these mechanisms. The strengths of this study lie in its prospective design, which enabled a comprehensive evaluation of the longitudinal impact of omalizumab and mepolizumab on both clinical outcomes and dynamic changes in T2 markers over a 12-month period. By including both blood eosinophils and total IgE levels as biomarkers, the study provides novel insights into their distinct associations with lung function improvements, particularly the predictive value of baseline blood eosinophils for FEV1 improvement in the omalizumab group and total IgE level reductions in the mepolizumab group. This biomarker-specific focus highlights the potential for personalized treatment strategies in T2-high severe asthma. However, this study has several limitations. The relatively small sample size may restrict the generalizability of the results and reduce statistical power for subgroup analyses. Furthermore, the study focused exclusively on omalizumab and mepolizumab, making it uncertain whether the findings are applicable to other biologics, such as anti-IL5α, anti-IL4α, or anti-TSLP therapies. Moreover, the underlying mechanisms specific to the observed FEV1 improvements with these biologics also remain unclear. Lastly, the observational design limits causal inferences, requiring validation through larger randomized controlled trials. 5 CONCLUSION In conclusion, this study highlights that omalizumab and mepolizumab improve clinical outcomes while exerting distinct effects on T2 markers, with dynamic changes uniquely correlating to clinical improvements in T2-high severe asthma. Baseline blood eosinophils were predictive of FEV1 improvement with omalizumab, while reductions in total IgE levels correlated with FEV1 improvement in mepolizumab-treated patients. These findings underscore the potential of biomarker-driven strategies for personalized asthma management. However, further research with larger randomized trials is needed to validate these results and explore the underlying mechanisms. AUTHOR CONTRIBUTIONS C.H.L. designed the study. C.H.L. performed the data analysis. C.H.L. interpreted the results of the statistical analysis. C.W.C. wrote the manuscript. C.H.L., S.W.W., S.E.T., and C.L.T. revised the manuscript critically for important intellectual contents. All authors contributed to the interpretations of the findings. All authors reviewed the manuscript. ACKNOWLEDGEMENTS We would like to thank Miss Hsiao-Huang Chuang for her assistance in applying for biological therapies through the National Health Insurance (NHI) program. FUNDING INFORMATION This study received funding from TSGH (TSGH-D-114257) and support from the Medical Affairs Bureau (MND-MAB-D-114078). CONFLICT OF INTEREST STATEMENT The authors have no relevant financial or non-financial interests to disclose. HUMAN ETHICS APPROVAL DECLARATION This study was reviewed and approved by the Institutional Review Board of Tri-Service General Hospital, Taipei, Taiwan (TSGHIRB No.: A202405141). The study utilized anonymized data, and informed consent was waived by the Institutional Review Board as per ethical guidelines. DATA AVAILABILITY STATEMENT The data supporting the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1 Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG. 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Omalizumab (n = 50) Mepolizumab (n = 40) p -value Age (years) 54.8 ± 14.9 57.0 ± 12.6 0.499 Sex (%) 0.132 Man 42.5 35.1 Woman 57.5 64.9 BMI (kg/m2) 26.0 ± 4.8 25.5 ± 3.3 0.620 Smoking state (%) 0.048 Never smoker 65 63 Former smoker 30 14 Current smoker 5 14 ACT score 15.3 ± 5.1 14.8 ± 4.0 0.704 FEV1/FVC preBD (%) 69.1 ± 14.5 68.8 ± 11.5 0.924 FEV1 preBD (L) 1.75 ± 0.9 1.53 ± 0.7 0.235 FEV1 preBD % predicted 64.4 ± 22.7 58.4 ± 18.9 0.224 Blood eosinophils (cells/μL) 268.2 ± 395.6 757.8 ± 684.1 < 0.001 Blood total IgE levels (IU/mL) 458.62 ± 348.1 620.5 ± 603.2 0.136 Exacerbations/ 6 months 2.6 ± 1.7 2.4 ± 1.4 0.438 fOCS (mg) 5.4 ± 5.3 7.9 ± 6.7 0.072 Baseline inhalers 0.119 ICS/LABA (%) 20 11 ICS/LABA/LAMA (%) 80 89 Data are presented as mean ± standard deviation, unless otherwise stated. p-values were calculated by independent t-test or Chi-square test. P < 0.05 are in bold. Abbreviations: ACT, asthma control test; preBD, pre-bronchodilator; BMI, body mass index; FEV1, forced expiratory volume in the first second; ICS, inhaled corticosteroid; LABA, long-acting bronchodilator; LAMA: long-acting muscarinic antagonist; OCS, oral corticosteroid. Figure legends Figure 1. Study Flow Diagram. Figure 2. Changes in clinical outcomes over 12 months in patients with T2-high severe asthma treated with omalizumab (A, C, E, G) and mepolizumab (B, D, F, H). Panels A and B represent the mean change in Asthma Control Test (ACT) scores at baseline, 6 months, and 12 months. Panels C and D show the mean change in forced expiratory volume in 1 second (FEV1, L) over the same time points. Panels E and F illustrate the mean change in the frequency of acute exacerbations, while panels G and H display the mean change in oral corticosteroid dose (mg). Statistical significance is indicated as * p < 0.05, * *p < 0.01, ** *p < 0.001, *** *p < 0.0001. Error bars represent standard deviations. Figure 3. Longitudinal changes in Type 2 (T2) inflammatory markers in T2-high severe asthma patients treated with omalizumab (A, C, E) and mepolizumab (B, D, F). Panels A and B show changes in blood eosinophil counts (cells/μL) at baseline, 6 months, and 12 months. Panels C and D display total IgE levels (KU/L) at the same time points. Panels E and F illustrate the correlation between baseline blood eosinophil counts and total IgE levels, with correlation coefficients ( r ) and p-values shown. Statistical significance is marked as * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, and ns = not significant. Error bars represent standard deviations. Figure 4. Correlation heatmaps showing the relationships between baseline and longitudinal changes in Type 2 (T2) inflammatory markers (blood eosinophils and total IgE levels) and clinical improvements (FEV1, ACT scores, exacerbation frequency, and steroid dose) in T2-high severe asthma patients treated with omalizumab (A) and mepolizumab (B). Positive correlations are shown in red, and negative correlations in blue, with color intensity representing the strength of the correlation. Significant correlations are marked with asterisks (* p < 0.05, ** p < 0.01, *** p < 0.001). Data include baseline blood eosinophil counts, blood eosinophil and total IgE level changes at 6 and 12 months, and corresponding clinical outcomes over time. Information & Authors Information Version history V1 Version 1 17 January 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords asthma treatment biologics eosinophils ige Authors Affiliations Chia-Wei Chang Tri-Service General Hospital Department of Internal Medicine Division of Pulmonary Medicine and Critical Care Medicine View all articles by this author Shin-Wei Wu Tri-Service General Hospital Department of Internal Medicine Division of Pulmonary Medicine and Critical Care Medicine View all articles by this author Shin-En Tang Tri-Service General Hospital Department of Internal Medicine Division of Pulmonary Medicine and Critical Care Medicine View all articles by this author Chen-Liang Tsai Tri-Service General Hospital Department of Internal Medicine Division of Pulmonary Medicine and Critical Care Medicine View all articles by this author Chia-Hsin Liu 0000-0002-8998-4098 [email protected] Tri-Service General Hospital Department of Internal Medicine Division of Pulmonary Medicine and Critical Care Medicine View all articles by this author Metrics & Citations Metrics Article Usage 260 views 106 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Chia-Wei Chang, Shin-Wei Wu, Shin-En Tang, et al. 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