Impact of Fluticasone Furoate/Vilanterol on Small Airway Function in Asthma: A Real- World Study Using Impulse Oscillometry Stratified by Eosinophilic Inflammation

Introduction

Asthma is a heterogeneous airway disease characterized by reversible airflow limitation and associated symptoms such as cough, wheezing, chest tightness, and dyspnea.¹ The underlying pathophysiology involves airway inflammation that affects both large and small airways. In recent years, the recognition of Type 2 (T2) inflammation, defined by elevated biomarkers such as blood eosinophils, fractional exhaled nitric oxide (FeNO), and serum periostin, has revolutionized the understanding and management of asthma.² Eosinophilic inflammation, a hallmark of T2-high asthma, has been associated with increased exacerbation risk, poor symptom control, and progressive structural changes in both central and small airways.³

Small airway dysfunction (SAD)—defined as impairment in the distal conducting airways (<2 mm)—plays a crucial role in asthma pathophysiology and is increasingly recognized as a determinant of disease severity and control.⁴ Traditional spirometry is often insensitive to SAD because of its predominant focus on large airway flow. In contrast, impulse oscillometry (IOS), a non-invasive technique based on forced oscillation, provides sensitive assessment of peripheral airway mechanics through parameters such as R5–R20 (frequency dependence of resistance), X5 (reactance at 5 Hz), and AX (reactance area).³ Evidence has demonstrated its strong correlation with SAD, making it widely applied in the detection of small airway involvement in asthma.^5–7

Inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combinations remain the cornerstone of controller therapy for persistent asthma.^8,9 However, differences in medication formulation and inhalation device design—such as metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and soft mist inhalers (SMIs)—may influence drug deposition within the airways and consequently affect therapeutic efficacy. Previous studies have shown that overall pulmonary deposition is lower with ICS/LABA delivered via DPI compared with SMI.^10,11 Whether this lower deposition rate has an impact on small airway function remains uncertain. Further investigation is needed to clarify whether differences in deposition across inhaler devices translate into clinically meaningful effects on small airway function. In the ETHA study,¹² patients with asthma treated with Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) via Ellipta showed significant improvements in small airway function.

Fluticasone furoate/vilanterol (FF/VI) delivered via the Ellipta device is a widely used once-daily ICS/LABA combination for asthma management. Previous studies have demonstrated its clinical benefits, including improvements in asthma symptoms, reduced rescue medication use, decreased exacerbation risk, and improved lung function, primarily based on conventional spirometric parameters such as FEV₁ and FVC.^8,13,14 However, the effects of FF/VI on small airway function have not been well explored, particularly when assessed using IOS. Preliminary studies suggest that patients with higher eosinophil levels may exhibit differential responses in small airway indices following ICS therapy.¹⁵ Our previous real-world study focused on clinical outcomes of ICS/LABA treatment¹⁶ but did not specifically evaluate small airway function. Therefore, we conducted a retrospective study to assess the effects of once-daily FF/VI 92/22 μg on small airway function in adult patients with asthma, stratified by blood eosinophil levels.

Materials and Methods

Study Patients

This retrospective observational study was conducted at a tertiary care center in Taiwan, specifically at the Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, and the Division of Chest Medicine, Department of Internal Medicine, Taichung. Patients were identified from October 2021 to March 2023.

Eligible participants were adults aged 20 years or older with a physician-diagnosed asthma, established based on compatible clinical features and objective pulmonary function findings. Diagnostic criteria included typical asthma-related symptoms (such as dyspnea, cough, sputum production, or wheezing) in conjunction with at least one of the following spirometric characteristics: diurnal peak expiratory flow variability exceeding 20% or a bronchodilator response defined as an increase in FEV₁ greater than 12% and 200 mL following inhalation of 400 μg salbutamol. Patients were required to have available IOS measurements and peripheral blood eosinophil data. Additional inclusion criteria comprised continuous treatment with FF/VI 92/22 μg for a minimum duration of 12 months and classification as Global Initiative for Asthma (GINA) step 3 or 4 disease. Patients meeting these criteria were enrolled for analysis.¹⁷ Only patients who were regularly followed in outpatient clinics and enrolled in a structured care program were included, supporting consistent treatment adherence. Patients with poor adherence, treatment duration of less than 12 months, or loss to follow-up were excluded. Patients with conditions that could potentially affect treatment response were also excluded, including those with autoimmune diseases (eg, systemic lupus erythematosus or Sjögren’s syndrome), those receiving biological therapies, and those with active malignancy.

A total of 113 adult patients with asthma were included. Based on baseline peripheral blood eosinophil levels, patients were categorized into a high eosinophil group (≥300 cells/µL; n = 48) and a low eosinophil group (<300 cells/µL; n = 65). All participants received once-daily FF/VI 92/22 μg via Ellipta for one year. Study outcomes were evaluated after 12 months of therapy and included IOS-derived indices, Asthma Control Test (ACT) scores, annualized exacerbation frequency, and spirometric parameters. In addition, the study examined whether blood eosinophil levels were associated with differences in small airway response to FF/VI. (Figure 1) The study protocol was approved by the Institutional Review Board of China Medical University Hospital (CMUH112-REC1-175), and the requirement for informed consent was waived due to the retrospective nature of the study.

Figure 1 Study design and patient flow of adults with asthma treated with fluticasone furoate/vilanterol 92/22 µg for one year.

Clinical Data Collection and Treatment Assessment

Baseline demographic and clinical information included age, sex, height, weight, body mass index (BMI), smoking status, comorbid conditions, peripheral blood eosinophil count, spirometric results, IOS parameters, ACT scores, and the number of acute exacerbations occurring in the year prior to treatment initiation. Following commencement of FF/VI therapy, patients were routinely followed at outpatient visits every 1 to 3 months.

At the 12-month follow-up, pulmonary function indices—specifically FEV₁, FVC, and the FEV₁/FVC ratio—as well as IOS parameters (R5%, R20%, R5–R20, X5, resonant frequency [Fres], and area of reactance [Ax]), ACT scores, annual exacerbation rates, and blood eosinophil counts were reassessed and compared with baseline measurements. Patients were defined as responders if improvement was observed in at least one small airway parameter derived from IOS, including R5–R20, Fres, or AX, based on within-subject changes from baseline. Improvements in conventional spirometric parameters, including FEV₁ and FVC, were analyzed separately as secondary outcomes. Patients without improvement in all IOS parameters were classified as non-responders.

Asthma Control Test (ACT)

Asthma symptom control was assessed using the Asthma Control Test, a validated five-item questionnaire addressing symptom frequency, activity limitation, rescue medication use, and patients’ overall perception of asthma control. ACT scores range from 5 to 25, with higher scores indicating better disease control. ACT assessments were performed during routine outpatient visits at intervals of 1 to 3 months. Baseline values were determined from medical records at the time of treatment initiation, and follow-up data were collected 12 months thereafter.

Acute Exacerbations (AEs)

Acute exacerbations were defined as episodes of progressive worsening of asthma symptoms, including dyspnea, cough, wheezing, or chest tightness, accompanied by deterioration in lung function. Exacerbation events were identified through systematic review of medical records. Mild exacerbations were defined as those requiring a short course of oral systemic corticosteroids, whereas moderate-to-severe exacerbations were defined by the need for increased bronchodilator therapy, emergency department visits, hospitalization, or systemic corticosteroid treatment for at least three consecutive days.¹⁸

Spirometry and Impulse Oscillometry (IOS)

Following initiation of FF/VI treatment, patients were regularly followed up at intervals of 1 to 3 months at our institution. Pulmonary function testing, including spirometry and IOS, was performed prior to treatment initiation to establish baseline values. All spirometry and IOS measurements were performed under clinically stable conditions, with no evidence of acute asthma exacerbation at the time of testing. All assessments were conducted using the same device (MasterScreen BODY/Diff with IOS module, CareFusion Germany GmbH, Hoechberg, Germany) for measurement consistency. Procedures were performed by trained and certified technicians in accordance with European Respiratory Society (ERS) recommendations and the manufacturer’s instructions.¹⁹ Quality control measures included proper patient posture, use of a nose clip, stable tidal breathing, and adequate cheek support to minimize upper airway shunting. Multiple technically acceptable measurements were obtained, and results were reviewed to ensure consistency and reproducibility. IOS parameters were measured according to standard recommendations and included R5 (% predicted resistance at 5 Hz), R20 (% predicted resistance at 20 Hz), R5–R20 (difference in resistance between 5 and 20 Hz, kPa/L/s), X5 (reactance at 5 Hz, kPa/L/s), resonant frequency (Fres, Hz), and the area of reactance (AX, kPa/L).The same assessments were repeated 12 months after treatment initiation, and all pulmonary function parameters were compared with baseline values.

Statistical Analysis

Continuous variables were summarized as mean ± standard deviation or median with interquartile range (IQR; 25th–75th percentile), depending on data distribution. Between-group comparisons were conducted using the independent-samples t-test for normally distributed variables and the Kruskal–Wallis test for non-normally distributed or ordinal variables. Categorical data were expressed as frequencies and percentages and analyzed using the chi-square test or Fisher’s exact test, as appropriate. Within-group changes from baseline to 12 months—including FEV₁, FVC, R5–R20, Fres, and annual exacerbation frequency—were assessed using paired-samples t-tests. Multivariable logistic regression analyses were performed to identify factors associated with small airway response to treatment. The dependent variable was responder status, defined as improvement in at least one small airway parameter derived from IOS, including R5–R20, Fres, or AX. Clinically relevant variables, including age, sex, smoking status, blood eosinophil count, baseline lung function, prior-year exacerbation frequency, and baseline ACT score, were included in the models. All statistical analyses were two-tailed, with statistical significance defined as a p-value ≤ 0.05. Analyses were performed using MedCalc for Windows, version 18.10 (MedCalc Software, Ostend, Belgium).

Results

Baseline Characteristics

A total of 113 adult patients with asthma were included in the analysis, comprising 48 patients in the high-eosinophil group (≥300 cells/µL) and 65 in the low-eosinophil group (<300 cells/µL). Baseline demographic and clinical features were similar between groups. The mean age was 44.1 years in the high-eosinophil group and 49.0 years in the low-eosinophil group, with no significant sex difference (25.0% vs. 32.3% male). Patients with higher eosinophil counts exhibited significantly greater serum immunoglobulin E levels compared with those in the low-eosinophil group (166 vs. 95.8 IU/mL, p = 0.002). The prevalence of comorbid allergic rhinitis, gastroesophageal reflux disease, chronic obstructive pulmonary disease, and bronchiectasis did not differ significantly. Baseline asthma control and lung function were comparable between groups: Asthma Control Test scores, annual exacerbation frequency, spirometric indices (FEV1, FVC), and IOS parameters (R5, R20, R5–R20, X5, Fres, and AX) showed no statistically significant differences. (Table 1)

Table 1 Baseline Characteristics of Study Participants

Changes in Pulmonary Function After One year of FF/VI Treatment

After 12 months of once-daily FF/VI treatment, significant improvements were observed in both spirometry and IOS indices. Mean FEV1 increased from 2.51 ± 0.74 L to 2.65 ± 0.79 L (p < 0.001), and percent predicted FEV₁ rose from 91.2% to 97.4% (p < 0.001). FVC increased from 3.16 ± 0.93 L to 3.23 ± 0.98 L (p = 0.0013), and percent predicted FVC improved from 96.5% to 99.2% (p < 0.001). IOS showed significant reductions in total and central airway resistance, with R5% decreasing from 148.2 ± 50.7 to 131.3 ± 29.7 (p < 0.001) and R20% from 145.5 ± 39.0 to 134.5 ± 29.8 (p < 0.001). The AX also declined significantly from 0.901 ± 1.14 to 0.699 ± 0.71 kPa/L (p = 0.044). Changes in R5–R20, X5, and resonant frequency (Fres) were not statistically significant. (Table 2) Among patients with blood eosinophil counts ≥300 cells/µL, FEV₁ rose from 2.64 ± 0.75 L to 2.75 ± 0.79 L (Δ = 0.109 L, p = 0.0016) and FVC from 3.24 ± 0.88 L to 3.30 ± 0.93 L (Δ = 0.061 L, p = 0.031). In those with eosinophil counts <300 cells/µL, FEV₁ improved from 2.41 ± 0.73 L to 2.59 ± 0.81 L (Δ = 0.174 L, p < 0.001) and FVC from 3.10 ± 0.97 L to 3.18 ± 1.01 L (Δ = 0.085 L, p = 0.015). These findings indicate that FF/VI 92/22 μg produced consistent improvements in spirometry function regardless of eosinophil status. (Figure 2) Patients with eosinophils <300 cells/µL exhibited significant improvement in both R5–R20 (0.086 ± 0.08 to 0.065 ± 0.07 kPa/L/s, p = 0.022) and Fres (16.2 ± 5.7 to 14.8 ± 5.6 Hz, p = 0.035). In contrast, patients with eosinophils ≥300 cells/µL showed no significant change in either R5–R20 or Fres. These findings suggest that improvement in small-airway mechanics with FF/VI 92/22 μg was observed in patients with lower eosinophilic inflammation. (Figure 3) Multivariable regression analysis did not identify any independent predictors of improvement in small airway parameters after adjustment for clinically relevant variables. (Supplementary Table 1)

Table 2 Changes in Spirometric and Impulse Oscillometry Parameters After One year of Treatment with FF/VI 92/22 µg

Figure 2 Changes in FEV1 and FVC after one year of treatment with fluticasone furoate/vilanterol 92/22 µg in asthma patients, stratified by eosinophil level. (A) Mean FEV1 (L) in all patients before and after treatment. (B) Mean FEV1 (L) in patients with eosinophils ≥300 cells/µL. (C) Mean FEV1 (L) in patients with eosinophils <300 cells/µL. (D) Mean FVC (L) in all patients before and after treatment. (E) Mean FVC (L) in patients with eosinophils ≥300 cells/µL. (F) Mean FVC (L) in patients with eosinophils <300 cells/µL.

Figure 3 Changes in small-airway impulse oscillometry indices (R5–R20 and resonant frequency) after one year of treatment with fluticasone furoate/vilanterol 92/22 µg in patients with asthma, stratified by eosinophil level. (A) R5–R20 (kPa/L/s) in all patients before and after treatment. (B) R5–R20 (kPa/L/s) in patients with eosinophils ≥300 cells/µL. (C) R5–R20 (kPa/L/s) in patients with eosinophils <300 cells/µL. (D) Resonant frequency (Fres, 1/s) in all patients before and after treatment. (E) Resonant frequency (Fres, 1/s) in patients with eosinophils ≥300 cells/µL. (F) Resonant frequency (Fres, 1/s) in patients with eosinophils <300 cells/µL.

Changes in Asthma Control and Exacerbation Frequency After FF/VI Treatment

After 12 months of treatment with fluticasone furoate/vilanterol 92/22 μg, the annual exacerbation rate and ACT scores were analyzed by eosinophil subgroup. Among patients with blood eosinophil counts ≥300 cells/µL, the annual exacerbation rate decreased from 0.06 ± 0.24 to 0.02 ± 0.14 events per year, although the difference did not reach statistical significance (p = 0.322). In contrast, patients with eosinophil counts <300 cells/µL demonstrated a significant reduction in exacerbations from 0.15 ± 0.40 to 0.04 ± 0.21 per year (p = 0.033). ACT scores remained stable in both groups, with no significant changes observed after treatment. The annual exacerbation rate decreased significantly in the low-eosinophil group, while Asthma Control Test scores remained stable (22.2 ± 3.1 to 22.6 ± 1.6 in the high-eosinophil group, p = 0.411; and 23.1 ± 1.4 to 22.9 ± 1.2 in the low-eosinophil group, p = 0.383). These results indicate that FF/VI was associated with a reduction in asthma exacerbations without altering overall symptom control scores. A reduction in exacerbations was observed in patients with lower eosinophil counts. (Table 3)

Table 3 Asthma Control and Annual Exacerbation Rate After One year of FF/VI 92/22 µg Treatment, Stratified by Blood Eosinophil Level

Discussions

This study provides real-world evidence on the effects of once-daily FF/VI 92/22 μg on spirometric and small-airway IOS parameters in adults with asthma. To the best of our knowledge, this is the first real-world study to evaluate the effects of FF/VI 92/22 μg on small airway function in patients with asthma. FF/VI treatment was associated with significant improvements in spirometric parameters, including FEV₁ and FVC, as well as reductions in total and central airway resistance (R5%, R20%) and reactance area. Improvements in small airway indices, including R5–R20 and resonant frequency, were observed in patients with lower blood eosinophil counts (<300 cells/µL). These findings suggest a potential association between eosinophilic status and differences in small airway response. In addition, a significant reduction in exacerbation frequency was observed in the low–eosinophil group, although this was not accompanied by a corresponding improvement in ACT scores. This may be partly explained by the generally low baseline exacerbation rates and well-controlled asthma status (ACT >20), suggesting a ceiling effect. In addition, the ACT may have limited sensitivity in detecting subtle clinical changes, particularly in relatively stable populations.

ICS/LABA combinations are the cornerstone of asthma management, available in various formulations differing in both pharmacologic components and inhaler devices. Previous studies have shown that ICS/LABA therapy improves lung function, reduces exacerbations, and enhances symptom control, mainly assessed by conventional spirometry parameters such as FEV1 and FVC.^20,21 Drug deposition within the respiratory tract is influenced by inhalation mechanisms and particle characteristics. For example, differences in deposition patterns have been reported among various inhaler types, including DPI, MDI, and SMI.¹⁰ However, the clinical implications of these differences, particularly in relation to small airway function, remain uncertain. Although previous studies have compared the clinical efficacy of different inhaled therapies,^20,21 evidence specifically addressing their effects on small airway function remains limited. In particular, data regarding the impact of FF/VI on small airway physiology remain scarce. Previous studies have evaluated FF/VI mainly in comparison with other ICS/LABA combinations. Hozawa et al compared FF/VI with budesonide/formoterol in a 4-week study of patients stepping up from medium-dose ICS monotherapy, showing that both regimens improved airway inflammation and small-airway indices, though greater reductions in FeNO and IOS parameters were observed with the budesonide/formoterol SMART regimen.²² More recently, Tanninen et al found that FF/VI and fluticasone propionate/formoterol achieved similar improvements in FEV₁ in adolescents with chronic bronchial obstruction, without significant benefit in small-airway indices.²³ In contrast, our real-world study demonstrated that once-daily FF/VI via the Ellipta device significantly improved both spirometry and IOS parameters in adults with asthma and was associated with reduced annual exacerbations. These findings extend prior short-term, controlled observations by providing longer-term and pragmatic evidence of small-airway improvement under routine clinical use.

In the CAPTAIN study, a higher dose of fluticasone furoate primarily reduced the rate of exacerbations and improved FEV₁, particularly in patients with elevated type 2 inflammatory biomarkers, such as baseline blood eosinophil counts ≥300 cells/μL and FeNO >50 ppb.²⁴ In our study, all patients received the same ICS dose (fluticasone furoate 92 μg). Interestingly, significant improvements in both proximal and distal airway function were observed in the low-eosinophil group, whereas these changes were not evident in the high-eosinophil group. Asthma patients with high type 2 inflammation often demonstrate inflammatory cell infiltration into the airway tissue, goblet cell hyperplasia with excessive mucus production, and epithelial barrier dysfunction, contributing to airway remodeling and bronchoconstriction, which in turn impair lung function and exacerbate symptoms.^25–27 Nevertheless, these patients generally respond better to ICS therapy, and increasing the ICS dose can improve clinical outcomes.^28,29 Our findings suggest that patients with higher blood eosinophil levels may exhibit a different small airway response, warranting further investigation. In the ETHA study, patients treated with FF/UMEC/VI for six weeks showed significant improvements in small airway function, as reflected by reductions in both pre- and post-bronchodilator R5 and R5–R19, regardless of baseline T2 inflammatory biomarker status.¹² The investigators suggested that the observed improvements in IOS parameters may have been largely attributable to the addition of a LAMA, which primarily targets airway caliber through bronchodilation independent of airway inflammation.^12,30 These findings reflect the observed effects of FF/VI delivered via the Ellipta device; however, the contribution of inhaler device characteristics to small airway response cannot be determined in the absence of direct comparative data. In patients with higher blood eosinophil levels, the potential role of treatment adjustments, such as increasing the inhaled corticosteroid dose or adding a LAMA, in improving small airway response remains to be determined.

There are several limitations to this study. First, this was a retrospective single-center study, which may introduce selection bias and limit generalizability. In addition, the absence of a control group limits the ability to establish causal relationships between FF/VI treatment and the observed changes in small airway function. Treatment decisions were influenced by clinical judgment, patient preference, and adherence, which may introduce variability. A relatively homogeneous population (GINA step 3–4) with regular follow-up was included to improve cohort consistency; however, residual confounding cannot be excluded. Finally, as only patients treated with FF/VI were included, the generalizability of these findings to other therapies remains uncertain. Second, small airway function was evaluated exclusively by IOS, without complementary methods such as imaging or tissue biopsy, and whether alternative approaches might reveal different findings requires further investigation. Third, although improvements in FEV₁ and FVC were observed across all patients, improvements in small airway parameters, such as R5–R20, were observed in patients with lower blood eosinophil counts. This finding suggests that eosinophilic status may be associated with differences in small airway response. However, blood eosinophil count was used as a single surrogate marker of eosinophilic inflammation in this study and does not fully capture the complexity of type 2 (T2) inflammatory status. Other biomarkers, such as FeNO and serum IgE, were not consistently incorporated into the analysis. Therefore, the classification of inflammatory phenotype may be incomplete, and the observed associations should be interpreted with caution. Future studies incorporating multiple biomarkers are warranted to provide a more comprehensive assessment of inflammatory phenotypes and their impact on treatment response.

Conclusion

In this study, FF/VI 92/22 μg delivered via the Ellipta device improved overall lung function in patients with asthma. Additional improvements in small-airway function were observed in patients with lower eosinophilic inflammation, suggesting that inflammatory phenotype may be associated with distal airway response. Further prospective studies are needed to clarify the role of inflammatory status in small airway dysfunction and to validate these findings.