Abstract Rationale Increased short-acting β2-agonist (SABA) use is a well-recognized risk factor for poor asthma outcomes. Patterns of SABA use and reduction in peak flow typically occur prior to the onset of exacerbations. Digital inhalers capture SABA use and inhalation parameters that enable predictive modeling to identify impending exacerbations. Methods We analyzed a 52-week single center observational cohort of adults with severe asthma using the ProAir® Digihaler (N = 86). The outcome was a SABA-defined clinical deterioration event (CDE) from previously specified Delphi rules. For each index day, we predicted whether a CDE would occur between day +5 and day +9 (5-day risk window with 5-day lead time). Predictors were recent SABA use and inhalation parameters over short-term and multi-week windows relative to each individual’s baseline. We trained an XGBoost classifier with a patient-level 80/20 split. The primary analysis was performed in those with uncontrolled asthma (ACT<19) on the held-out test set. We reported ROC AUC (95% CI) and Brier score. A single threshold chosen on training was carried forward to test for sensitivity/specificity. Separately, in an exploratory analysis, we used the same approach to classify whether the model can predict OCS-exacerbations during the 52-week follow-up. This analysis used the same 80/20 split and was evaluated using ROC AUC. Results Our model achieved AUC 0.878 (95% CI 0.867-0.890) for predicting CDEs 5-9 days ahead. Calibration was strong (Brier = 0.092). Using a training-selected operating point near p≈0.213, test performance was sensitivity 0.84 and specificity 0.79. We utilized the same machine learning algorithm to predict OCS-requiring exacerbations over the 52-week follow-up period and the model was not predictive (AUC=0.525). Conclusions In uncontrolled asthma, digital inhaler parameters provide a high-discrimination, well-calibrated signal for early deterioration. These findings reinforce that patterns over time in SABA use and inhalation characteristics can identify early markers of decline offering an opportunity for intervention. Predictive models can be used to develop alerts that could drive interventions such as automated outreach, adherence coaching, and changes to treatment during early clinical deterioration. This abstract is funded by: The original study was funded by Teva Pharmaceuticals.

Abstract Rationale Traditionally used spirometry parameters, such as forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25 and 75% (FEF25-75%) of forced vital capacity (FVC), may be misleading in informing asthma treatment decisions. Spirometry-derived ratios are better at assessing changes in airway function relevant to asthma control. In particular, FEF25-75% is highly volume dependent, but it may be more valuable when adjusted for the volume as in the ratio FEF25-75%/FVC. We evaluated the effect of dupilumab on spirometry-derived ratios in patients with asthma and assessed the relationship between changes in these ratios and changes in fractional exhaled nitric oxide (FeNO) and eosinophil count. Methods In the phase 4 VESTIGE study (NCT04400318), adults with uncontrolled, type 2 (eosinophils ≥300 cells/µL and FeNO ≥25 ppb), moderate-to-severe asthma received dupilumab 300 mg (n = 72) or placebo (n = 37) every 2 weeks for 24 weeks. We calculated pre-bronchodilator ratios as FEV1/FVC (reflecting large airways) and FEF25-75%/FVC (small airways). We used a penalized regression spline model to evaluate the relationships between changes in these ratios and changes in FeNO and eosinophil count from baseline to Week 24. Results Baseline ratios were similar in the dupilumab and placebo groups but differed significantly in both groups by Week 24. The baseline mean (standard deviation [SD]) FEV1/FVC ratio was 60.7% (11.5) with dupilumab and 61.8% (13.9) with placebo; at Week 24, dupilumab vs placebo improved the ratio by a least squares mean difference (LSMD) of 6.8% [95% CI: 3.4, 10.2]; P<0.001. The baseline mean (SD) FEF25-75%/FVC ratio was 34% (24) with dupilumab and 37.8% (25.9) with placebo; at Week 24, dupilumab vs placebo improved by an LSMD of 12.2% [5.2, 19.1]; P<0.001. As the fold change from baseline at Week 24 in eosinophil count increased (Figure), the value of each spirometry ratio decreased (i.e. lung function worsened) with placebo but was stable with dupilumab. Hence, large and small airway function improved regardless of increasing eosinophil count in patients who received dupilumab but not in those who received placebo. Similarly, both ratios improved from baseline for all fold changes in FeNO for the dupilumab group but not the placebo group. Conclusion Dupilumab vs placebo significantly improved spirometry-derived ratios at Week 24, indicating improved large and small airway function, while the beneficial effect of dupilumab relative to baseline was similar for all patients regardless of their change in eosinophil count. This abstract is funded by: Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Abstract Background Asthma related healthcare utilization remains a leading cause of preventable emergency department (ED) visits and hospitalizations. Despite effective asthma maintenance therapy, oral corticosteroid (OCS) use is common, is associated with significant side effects, and reflects suboptimal asthma control. Existing asthma performance measures emphasize maintenance controller use including inhaled corticosteroids and adherence rather than OCS burden, leaving steroid-reliant care unflagged. Using prescription claims data, we developed a new performance measure of OCS use (OCS Stewardship Measure) in asthma patients to determine whether it is predictive of future outcomes, responsive to year-to-year change, and actionable to improve care. Method We conducted a retrospective cohort study using administrative claims from Blue Cross Blue Shield of Michigan, provided by the Michigan Value Collaborative. Patients (≥2 years old on 1/1/2023) with asthma diagnosis and pharmacy claims data in 2022 through 2024 were included. Patients with chronic conditions requiring systemic steroids for non-asthma treatment (e.g. autoimmune), and steroid prescriptions associated with non-asthma diagnoses (e.g. dermatitis) were excluded. OCS prescriptions were categorized as 0, 1, ≥2 in 2023 and the primary outcome was asthma related ED visits and hospitalizations in 2024. We also evaluated how year-over-year changes in OCS was associated with subsequent healthcare utilization. Analysis was adjusted for age, sex, Charlson Comorbidity Index (CCI), and controller/reliever prescriptions. Adult and pediatric patients were analyzed separately. Results The cohort included 30,079 patients: 23,063 adults (mean age 50±16.3) and 7,016 children (mean age 9.4±4.5). Compared to those with no OCS prescriptions in 2023, patients with ≥2 prescriptions had significantly higher risk of ED visits or hospitalizations in 2024 (OR 2.36; 95% CI 2.00-2.78). This risk increased with more OCS prescriptions (Figure 1). Additionally, patients with ≥2 OCS prescriptions in 2022 but lowered to 0 or 1 OCS prescriptions in 2023 had significantly lower asthma related healthcare utilization in 2024 (OR 0.49; 95% CI 0.37-0.65) compared to patients that maintained ≥2 OCS prescriptions. In adults, 21.1% of patients with ≥2 OCS prescriptions [n = 4,039 (17.5%)] in 2023 did not have an inhaled corticosteroid controller fill. Results were similar in the pediatric population. Conclusion The OCS Stewardship Measure can be calculated using administrative claims data to reliably identify high-risk asthma patients likely to have subsequent healthcare utilization, reflect clinical changes, and reveal actionable care gaps. Tracking OCS use could enable health systems to more effectively monitor asthma care at a population level. This abstract is funded by: Blue Cross Blue Shield of Michigan (BCBSM) Value Partnership Program

Abstract Rationale Regular short-acting β2-agonist (SABA) use leads to β2-receptor downregulation, reduced bronchoprotection, rebound hyper-responsiveness, and increased eosinophilic inflammation. Excessive SABA use correlates with higher risks of asthma exacerbations, hospitalizations, and mortality. Consequently, SABA monotherapy is no longer the preferred reliever per current guidelines. In this health system-wide quality improvement (QI) initiative, we analyzed SABA refill prescription patterns among specialist-treated asthma patients (Allergy-Immunology, Adult and Pediatric Pulmonology) before and after a direct campaign to reduce SABA prescribing practices. Data from primary care asthma patients were included for comparison. Methods Electronic Health Record (EHR) data were extracted to create a project dashboard. Analyses included asthma patients aged ≥12 years, seen at least twice within two years, categorized by specialty. Baseline “canister count” represented the total of prescribed inhalers plus available refills. Patients were categorized by annual canister counts with ≥3 canisters/year identified as the threshold for potential harm. We also assessed trends in new albuterol prescriptions, and prescriptions allowing >3 canisters/year. SABA prescribing practices were compared by specialty before and after provider/clinic education campaigns, focused patient instruction tools for AIR (Anti-inflammatory Relievers), and EHR-based best practice alerts and Smart Order Sets. Results In September 2023, 1,949 specialist-treated asthma patients were analyzed. Overall, 81% received ≥3 SABA canisters/year—70% in Allergy-Immunology, 90% in Adult Pulmonology, and 97% in Pediatric Pulmonology. A provider survey (n = 92) revealed limited awareness of the specific ≥3 canister/year harm threshold, though most respondents recognized general SABA-related harm and benefits of steroid-based relievers. Following interventions, Adult and Pediatric Pulmonary services demonstrated improvement in prescribing patterns, with Adult Pulmonary showing a marked reduction in SABA prescriptions—lower than rates observed in Primary Care. The increase in Allergy is being evaluated but felt related to updates needed in nursing protocols for example. Trends indicated an overall decrease in high (≥3 canister/year) SABA refill rates, suggesting increasing impact of the initiative over time (Table 1). Conclusion A coordinated, health system-supported QI initiative can reduce excessive SABA prescribing. However, the magnitude of improvement varies by subspecialty and patient population. Tailored interventions and sustained data feedback are critical to optimizing reliever therapy in alignment with GINA recommendations. Disseminating and adapting such strategies across systems may further advance rational SABA use and improve asthma outcomes. This abstract is funded by: Department of Internal Medicine Quality Improvement (QI) Faculty Award

Abstract Rationale A subset of patients with severe asthma (SA) remain inadequately controlled despite use of targeted biologic therapies. In these refractory cases, dual biologic therapy has emerged in clinical practice. However, there are no formal guidelines for routine dual-biologic use owing to limited evidence on safety, efficacy, and patient selection. We sought to characterize real-world dual biologic use, including patient profiles, treatment patterns, biomarker profiles, and change in exacerbation burden. Methods We conducted a retrospective analysis of a cohort of adult patients with moderate to severe asthma who received ≥3 months of overlapping biologic therapy for asthma and/or comorbid atopic conditions. Patients were identified via Electronic Health Record query, manual chart review, and from a cohort enrolled into the CHRONICLE registry at our site (NCT03373045). We captured demographics, comorbidities, concomitant asthma medications, biomarkers (blood eosinophil count (BEC), total Immunoglobulin E (IgE), fractional expired nitric oxide (FeNO)), spirometry (Forced Expiratory Volume in 1 second (FEV1) % predicted and liters, and asthma exacerbations rate. Exacerbations were identified for the 12 months pre and post dual-biologic initiation. Primary outcome was change in annualized asthma exacerbations rate (AAER) 12 months pre- vs post-initiation; paired t-tests and Wilcoxon signed-rank tests were used for analysis. Results Among 24 patients meeting inclusion criteria, the median age at dual biologic initiation (i.e., baseline) was 51 years (IQR: 44-56), 88% identified as White and 79% of patients were female. The median BEC was 1 cell/μL (n = 21), blood IgE was 58 IU/mL (n = 20), and FeNO was 31 ppb (n = 21). The median FEV₁ was 1.87 L and 64% (n = 20). All patients were on ICS-containing inhalers, and 46% were maintained on daily oral corticosteroids. The most common respiratory comorbidities included allergic rhinitis (n = 21), chronic rhinosinusitis (n = 17) and obstructive sleep apnea (n = 14). The most frequently prescribed dual biologic combinations were dupilumab/tezepelumab (n = 9), benralizumab/tezepelumab (n = 4), and dupilumab/benralizumab (n = 3). AAER declined following initiation of dual biologic therapy from 1.67 (±1.63) in the 12 months prior to baseline to 0.96 (±1.23) after one year of dual therapy, representing a 42.5% relative reduction. These reductions were statistically significant by both paired t-test (p = 0.0234) and Wilcoxon signed-rank test (p = 0.0276). Conclusions Dual-biologic therapy was associated with a reduction in exacerbations. These findings suggest potential clinical benefits of dual biologic therapy in SA with refractory disease on a single biologic. This abstract is funded by: None

Rationale. Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin, offers a promising treatment for severe asthma (SA). However, real-world experiences evaluating reasons for its discontinuation is lacking. Understanding the reasons for discontinuation requires scrutiny given its impact of clinical practice. Methods. This is a retrospective analysis of real-world data involving 129 SA patients treated with Tezepelumab. Data includes demographics, comorbidities, asthma medications (including prior biologic use), spirometry, exacerbation history, Asthma Control Test (ACT) scores, and biomarkers (immunoglobulin E (IgE), blood eosinophils count (BEC)), and fractional exhaled nitric oxide (FeNO). Results. Our cohort included 129 older patients (Mean Age=53.4±14.4 yrs.), with T2 (Type2)-inflammation (Historic high BEC=500±800 cells/µL; FeNO=22±18ppb), poor symptom control (ACT=11.7±4.3), history of frequent exacerbations (2.4±2.11 in the previous 12 months), and low FEV1 (75.8±26.9%) at baseline. Overall, 44 (34%) patients discontinued Tezepelumab. Among the discontinuers, 82% had previous biologic treatment. There were no statistically significant differences in age, BMI, smoking history, BEC, FeNO, ACT, or exacerbation rates between the two groups (continuers vs. discontinuers). A higher proportion of patients with atopy (prior positive skin prick test or in-vitro allergy testing) discontinued treatment (42% vs. 28% of continuers), but this difference was not statistically significant (p=0.11). Discontinuers had significantly lower mean FEV1 levels at baseline than continuers when measured in L (1.9±0.9L vs. 2.3±1.0L; p=0.04), but not as FEV1 % predicted (71.2±26.4% vs. 78.0±27.1%; p=0.17). The most common reasons for discontinuation included reported lack of benefit (n=25, 57%) and adverse reactions other than anaphylaxis (n=10, 23%). Other reasons included cost (n=5, 11%), anaphylaxis (n=2, 5%), and miscellaneous (n=2, 5%). Treatment duration varied. Patients who discontinued due to lack of benefit (8.4±4.8 mo.) and cost (6.8±7.0 mo.) remained on treatment the longest. Patients who discontinued due to other adverse reactions remained on treatment for an average of 6.1±5.3 months. Conclusion. Our study offers novel insights into real world experience with Tezepelumab discontinuation. Approximately one-third of asthma patients discontinued Tezepelumab. The most common reason for discontinuation was a perceived lack of benefit, with lower raw FEV1 measurements significantly associated with discontinuation. The timetil discontinuation varied, but those discontinuing for lack of benefit remained on treatment the longest. Cost is also a factor, with approximately 10% of patients who discontinue Tezepelumab due to expense.

Rationale: Current asthma management often relies on cross-sectional biomarker assessment for phenotyping and biologic selection. Tezepelumab is typically prescribed for non-T2 asthma;. However, we challenge this approach by evaluating longitudinal trends in key biomarkers—blood eosinophils counts (BEC), Immunoglobulin E (IgE), and Fractional Exhaled Nitric Oxide (FeNO)—and analyzing Tezepelumab's impact on exacerbations, Asthma Control (assessed by ACT scores), and Force Expiratory Volume in 1 second (FEV1)). Methods: This real-world cohort involved severe asthma (SA) patients treated with Tezepelumab. Data includes demographics, lung function, exacerbation history, ACT, and biomarkers (IgE, BEC, FeNO). Baseline was defined as the first administration of Tezepelumab. Follow up data was collected from subsequent clinic visits. Linear mixed effects models were used to analyze the interactions of biomarkers with outcomes and exacerbations, asthma control and FEV1 lung function. The model outcome was the change in value from baseline at one year. For each model, main effects for the predictor of interest (BEC, IgE, and FeNO) were tested, as well as interactions with these predictors over time. These interactions indicate if the relationship between predictors at baseline and follow-up differs. For exacerbation change, linear regression was used to compare the exacerbation rate change from baseline. Results: This study included 129 SA patients, averaging 53.4±14.4 years old with BMI of 34.2±8.3. Most (79%) had previously used biologics. The cohort had a high disease burden, averaging 2.4±2.1 exacerbations in the year before baseline. A significant effect was observed in ACT (F(2,121)=4.11, p=0.0187). Baseline BEC levels did not significantly influence ACT (p=0.1111), and interactions with time were also not significant (p=0.5150). IgE and FeNO interactions did not yield significance in ACT trends. Time showed a significant effect on ACT (p=0.0078 for IgE, p=0.0166 for FeNO). FEV1 did not show significant differences across biomarkers. Notably, exacerbation rates differed significantly by baseline BEC (F(2,118)=10.77, p<0.0001) and FeNO (p<0.0001), supporting biomarker-based variability in exacerbation frequency. Conclusion: While ACT score changes appeared to interact with IgE, no interaction was observed with BEC or FeNO. Exacerbation rates demonstrated potential interaction with BEC and FeNO, but not IgE. FEV1 did not interact with any biomarker model. These findings suggest that while certain biomarkers may provide insights into ACT and exacerbation trends with Tezepelumab, FEV1 outcomes remain unaffected by biomarker variability. This underscores the utility of specific biomarkers in guiding Tezepelumab therapy and highlights the need for a refined approach in using biomarkers to predict clinical outcomes.

RATIONALE Biologic therapies are effective in reducing exacerbations in patients with severe asthma (SA). In a previous descriptive analysis, we found greater exacerbation reductions in patients who started biologics <3 years after date of SA onset compared with ≥3 years. This multivariable analysis evaluated the independent effect of time since SA onset adjusting for the effects of other factors. METHODS The CHRONICLE study (NCT03373045) is an ongoing, observational study of US adults with SA treated by allergists/immunologists or pulmonologists. This analysis evaluated patients enrolled in CHRONICLE from February 2018 to February 2024 who initiated biologic treatment and had complete data. Asthma exacerbations and medications for 12 months before enrollment and every 6 months after enrollment were reported, as well as the estimated date of SA onset based on when a patient was first treated with high-dosage inhaled corticosteroids with additional controllers. Factors with a univariate association (P<0.1) with on-treatment (while receiving a biologic) exacerbation rate during the 12 months post-initiation were included in a multivariable model to identify independent, statistically significant associations. A locally estimated scatterplot smoothing (LOESS) analysis plotted the relationship between percentage exacerbation rate reduction and time from date of SA onset to biologic initiation. The exacerbation rate reduction was calculated by comparing the rates for the 12 months before and 12 months after biologic initiation. RESULTS Selected univariate factors were race, age at first asthma diagnosis, age at biologic initiation, age at screening, time from date of SA onset to biologic use, and exacerbation count during the 12 months before biologic initiation. Multivariable analyses demonstrated a significant association between the time from date of SA onset to biologic initiation (in years) and exacerbations in the 12 months after biologic initiation (rate ratio: 1.04, P<0.001). Black race was also significantly associated with on-treatment exacerbation rate compared with White race (2.40, P<0.01), as was exacerbation count in the 12 months before biologic initiation (1.48, P<0.0001). LOESS analysis showed diminished exacerbation reduction (decreased biologic effectiveness) with increasing time between date of SA onset and biologic initiation. CONCLUSION Adjusting for other factors, shorter time from date of SA onset to biologic initiation was associated with a lower on-treatment exacerbation rate and increased biologic effectiveness. These findings underscore the value of timely access to biologic treatments for eligible patients with SA and may support earlier incorporation of biologics in stepwise therapy guidelines.