Severe Asthma Patients Research Articles

Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma

Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P< .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.

Thrombin induces IL-8/CXCL8 expression by DCLK1-dependent RhoA and YAP activation in human lung epithelial cells

BackgroundDoublecortin-like kinase 1 (DCLK1) has been recognized as a marker of cancer stem cell in several malignancies. Thrombin is crucial in asthma severity as it can promote IL-8/CXCL8 production in lung epithelial cells, which is a potent chemoattractant for neutrophils. However, the pathologic role of DCLK1 in asthma and its involvement in thrombin-stimulated IL-8/CXCL8 expression remain unknown.MethodsIL-8/CXCL8, thrombin, and DCLK1 expression were observed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. A549 and BEAS-2B cells were either pretreated with inhibitors or small interfering RNAs (siRNAs) before being treated with thrombin. IL-8/CXCL8 expression and the molecules involved in signaling pathway were performed using ELISA, luciferase activity assay, Western blot, or ChIP assay.ResultsIL-8/CXCL8, thrombin, and DCLK1 were overexpressed in the lung tissues of severe asthma patients and ovalbumin (OVA)-induced asthmatic mice model. Our in vitro study found that DCLK siRNA or LRKK2-IN-1 (DCLK1 inhibitor) attenuated IL-8/CXCL8 release after thrombin induction in A549 and BEAS-2B cells. Thrombin activated DCLK1, RhoA, and YAP in a time-dependent manner, in which DCLK1 siRNA inhibited RhoA and YAP activation. YAP was dephosphorylated on the Ser127 site after thrombin stimulation, resulting in YAP translocation to the nucleus from the cytosol. DCLK1, RhoA and YAP activation following thrombin stimulation were inhibited by U0126 (ERK inhibitor). Moreover, DCLK1 and YAP siRNA inhibited κB-luciferase activity. Thrombin stimulated the recruitment of YAP and p65 to the NF-κB site of the IL-8/CXCL8 promoter and was inhibited by DCLK1 siRNA.ConclusionsThrombin activates the DCLK1/RhoA signaling pathway, which promotes YAP activation and translocation to the nucleus from the cytosol, resulting in YAP/p65 formation, and binding to the NF-κB site, which enhances IL-8/CXCL8 expression. DCLK1 might be essential in thrombin-stimulated IL-8/CXCL8 expression in asthmatic lungs and indicates a potential therapeutic strategy for severe asthma treatment.

Epidemiology, treatment and health care resource use of patients with severe asthma in Germany – a retrospective claims data analysis

Background Asthma causes various clinical symptoms, including unpredictable severe exacerbations, and even though most patients can achieve a reasonable disease control due to adequate treatment, some patients do not. This study seeks to describe healthcare resource utilization (HCRU) and treatment of asthma and severe asthma patients in Germany. Method A retrospective claims data analysis has been conducted on adult asthma patients and a subset of patients with severe asthma, identified during July 2017 – June 2018. A proxy was used to identify severe asthma patients based on therapy options recommended within the German treatment guideline for treating these patients. These include (i) biologics, (ii) medium/high-dose inhaled corticosteroids (ICS) in conjunction with LABA/montelukast and antibiotics/oral corticosteroids (OCS), and (iii) long-term OCS therapy. HCRU and treatment of patients were observed during a 1-year follow-up period (July 2018 – June 2019). Results The study included 388 932 adult asthma patients (prevalence: 7.90%), with 2.51%-12.88% affected by severe asthma (depending on the definition). 22.60% of all asthma patients experienced hospitalizations (severe asthma: 36.11%). Furthermore, 13.59% received OCS (severe asthma: 39.91%), but only 0.18% (severe asthma: 1.25%) received biologics. Only 23.95% (severe asthma: 41.17%) visited a pulmonologist. Conclusions A considerable proportion of severe asthma patients receive long-term OCS therapy. However, less than 50% have seen a pulmonologist who would typically seek a change in treatment to avoid the long-term consequences of OCS. To optimize the treatment of severe asthma in Germany, better referral of these patients to specialists is needed and considering potential treatment alternatives.

Identification of Molecular Markers Related to Immune Infiltration in Patients with Severe Asthma: A Comprehensive Bioinformatics Analysis Based on the Human Bronchial Epithelial Transcriptome.

Severe asthma (SA), a heterogeneous inflammatory disease characterized by immune cell infiltration, is particularly difficult to treat and manage. The airway epithelium is an important tissue in regulating innate and adaptive immunity, and targeting airway epithelial cell may contribute to improving the efficacy of asthma therapy. Bioinformatics methods were utilized to identify the hub genes and signaling pathways involved in SA. Experiments were performed to determine whether these hub genes and signaling pathways were affected by the differences in immune cell infiltration. The weighted gene coexpression network analysis identified 14 coexpression modules, among which the blue and salmon modules exhibited the strongest associations with SA. The blue module was mainly enriched in actomyosin structure organization and was associated with regulating stem cell pluripotency signaling pathways. The salmon module was mainly involved in cornification, skin development, and glycosphingolipid biosynthesis-lacto and neolacto series. The protein-protein interaction network and module analysis identified 11 hub genes in the key modules. The CIBERSORTx algorithm revealed statistically significant differences in CD8+ T cells (P = 0.013), T follicular helper cells (P = 0.002), resting mast cells (P = 0.004), and neutrophils (P = 0.002) between patients with SA and mild-moderate asthma patients. Pearson's correlation analysis identified 11 genes that were significantly associated with a variety of immune cells. We further predicted the utility of some potential drugs and validated our results in external datasets. Our results may help provide a better understanding of the relationship between the airway epithelial transcriptome and clinical data of SA. And this study will help to guide the development of SA-targeted molecular therapy.

Diagnosis and treatment of adult asthma patients in Serbia: a 2022 experts group position statement

ABSTRACT Introduction Asthma is the most common non-communicable chronic lung condition across all ages. Epidemiological data indicate that many asthma patients in Serbia remain undiagnosed and untreated. The implementation of recent global advances in asthma management is limited due to the lack of a systematic approach, drug availability and regulatory affairs. In addition, the global coronavirus disease pandemic has posed a significant challenge, particularly in resource-limited settings. Areas covered In this paper, we propose an algorithm for treating adult asthma patients in Serbia. We performed PubMed database search on published asthma clinical trials and guidelines from 1 January 2015 to 10 March 2020. The consensus process incorporated a modified Delphi method that included two rounds of e-mail questionnaires and three rounds of national asthma expert meetings. We focus on 1) objective diagnosis of asthma, 2) the implementation of up-to-date therapeutic options, and 3) the identification and referral of severe asthma patients to newly established severe asthma centers. Expert opinion Regional specificities and variations in healthcare systems require the adaptation of evidence-based knowledge. Practical, clinically oriented algorithms designed to overcome local barriers in healthcare delivery may facilitate timely and adequate asthma diagnosis and the local implementation of current advances in asthma management.

IF AT FIRST YOU DON'T SUCCEED, TRY TRY AGAIN!

<h3>Introduction</h3> Current asthma guidelines recommend trying a biologic in severe persistent asthmatic patients for six months before switching to a different one. We report a patient who was trialed on no less than three biologics without success until finally improving after treatment with a fourth. <h3>Case Description</h3> 63 year-old male with severe persistent asthma presented using his Albuterol MDI ten times a day with nightly awakenings, despite treatment with high dose Budesonide/Formoterol and Montelukast. He required Prednisone bursts four times a year for asthma exacerbations. His total IgE was 539 with positive serum tests to aeroallergens. Omalizumab was initiated with mild improvement for a few months, but his asthma symptoms returned to baseline after one year of treatment. His absolute eosinophil count was 1,100. He was started on Mepolizumab but developed a rash after the first dose and dyspnea and rash after the second, prompting discontinuation. Patient then tried Benralizumab for a year without improvement. Lastly, Dupilumab was started and his asthma markedly improved, i.e. he was able to sleep through the night, his rescue MDI decreased to two times a week, and he has not required Prednisone in several months. <h3>Discussion</h3> It took trialing four different biologics before finding a therapeutic intervention that worked. It is important to be persistent and flexible when finding treatment options for difficult-to-treat severe asthmatic patients.

GAPS IN CLINICAL CARE ESCALATION AMONG SEVERE, PERSISTENT ASTHMA PATIENTS FOLLOWING INDICATORS OF UNCONTROLLED ASTHMA

<h3>Introduction</h3> Approximately 5-10% of patients with asthma have severe asthma (SA). Standard of care recommends escalation of care with uncontrolled disease. To evaluate current gaps in care in the US, this analysis examined care received among SA patients following events indicating uncontrolled disease (EUD). <h3>Methods</h3> Administrative claims databases for SA patients with Medicare Fee-for-Service, Medicare Advantage, Managed Medicaid, or commercial insurance spanning 2015-2020 were utilized. Severe, persistent asthma patients were indexed hierarchically on asthma-related EUD: ≥1 hospitalization, ≥2 emergency department (ED) visits with systemic corticosteroid treatment (SCS), 1 ED + ≥1 outpatient (OP) visit with SCS, or ≥2 OP visits with SCS. SA patients without any events were matched as controls. All were required to be 12+ years old, have 12 months enrollment pre- and post-index, and have no other major respiratory disease or biologic treatment during the pre-period. Specialist visits and medication escalation were examined during the post-index period. <h3>Results</h3> 181,548 SA patients were identified (90,774 uncontrolled, 90,774 controlled). Across payer channels, 33-51% of uncontrolled SA patients presented no specialist nor medication escalation intervention (Figure). Patients with 2 ED visits were most likely to present an absence of any intervention. <h3>Conclusion</h3> Results demonstrate that a substantial portion of uncontrolled SA patients do not have evidence of care escalation following uncontrolled disease, highlighting substantial gaps in care. Guidelines in the US recommend referral to an asthma specialist for systematic assessment or co-management for all SA patients, particularly those with uncontrolled disease. Accelerating subspecialist referrals and/or medication escalation may improve asthma care.

PATIENT-REPORTED TRIGGER NUMBER IS A STRONG PREDICTOR OF UNCONTROLLED DISEASE AMONG PATIENTS WITH SEVERE ASTHMA

<h3>Introduction</h3> Severe asthma (SA) is associated with high morbidity. Numerous factors can trigger or exacerbate asthma symptoms and attacks through interactions with the airway epithelium. A better understanding of triggers among SA patients could help improve care. <h3>Methods</h3> CHRONICLE is an observational study of adults with SA receiving biologics, maintenance systemic corticosteroids (SCS), or uncontrolled on high-dosage inhaled corticosteroids and additional controllers. For patients enrolled February 2018–February 2021, this analysis examined associations between the number of patient-reported triggers (from a 17-category survey) and disease control (Asthma Control Test [ACT], work productivity, Saint George's Respiratory Questionnaire [SGRQ], HCP-reported exacerbations). Multivariate analyses further examined associations between disease control and trigger number or blood eosinophil counts [BEC]. <h3>Results</h3> Among 2847 enrolled patients, 1434 (51.3%) completed the triggers questionnaire. Median trigger number per patient was 8 (IQR: 5, 10). Most common triggers were weather/air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, reduced work productivity, and more exacerbations (<b>Figure</b>), which was confirmed by multivariate models. For all measures, trigger number was a stronger predictor than BEC. AUC-ROC for trigger number was higher than for BEC for predicting ≥1 exacerbations and ≥1 asthma hospitalizations (0.60 vs. 0.53 and 0.67 vs. 0.51, respectively). <h3>Conclusion</h3> Among US specialist-treated patients with SA, number of patient-reported triggers was a better predictor than BEC of disease morbidity across multiple measures. This highlights the importance of understanding patient-reported triggers in SA treatment.

Cost-effectiveness of benralizumab versus mepolizumab and dupilumab in patients with severe uncontrolled eosinophilic asthma in Spain

Objective To assess the cost-effectiveness of benralizumab (benra) vs. mepolizumab (mepo) and dupilumab (dupi) for the treatment of patients with severe uncontrolled asthma from the Spanish Health System perspective. Methods Exacerbations avoided, quality-adjusted life years (QALYs) gained and costs in a 5-year period were estimated with a Markov model for a cohort of 1,000 patients in which, based on published evidence, 31% of the patients received biologics + oral corticosteroids (OCS) and 69% received only biologics. Efficacy data (exacerbation reduction and OCS elimination) were derived from a matching-adjusted indirect comparison. Published EQ-5D utilities per health state (biologic alone, biologic + OCS, standard of care + OCS, exacerbations, and post-exacerbations) were used for QALY estimation. Utility decrements associated with exacerbation management [-0.1 (OCS or emergency visits), −0.2 (hospitalization)] derived from the literature were applied. Costs (€, 2022) included drug acquisition (ex-factory price), administration and disease management. An expert panel (2 pneumologists and 1 pharmacist) validated all inputs. Results Benra was more effective (52.21 QALYs) than mepo (51.39 QALYs) and dupi (51.30 QALYs). Benra avoided more exacerbations (2.87 exacerbations) compared to mepo (4.70 exacerbations) and dupi (5.11 exacerbations) for the 5-year horizon. Total costs/patient were €56,093.77 (benra), €59,280.45 (mepo) and €62,991.76 (dupi), resulting in benra dominating (more QALYs with lower costs) vs. mepo and dupi. Conclusions Benralizumab can be considered as a dominant treatment alternative vs. other biologic drugs for the treatment of uncontrolled severe eosinophilic asthma patients in Spain.

Identification of miRNA-mRNA-TFs regulatory network and crucial pathways involved in asthma through advanced systems biology approaches.

Asthma is a life-threatening and chronic inflammatory lung disease that is posing a true global health challenge. The genetic basis of the disease is fairly well examined. However, the molecular crosstalk between microRNAs (miRNAs), target genes, and transcription factors (TFs) networks and their contribution to disease pathogenesis and progression is not well explored. Therefore, this study was aimed at dissecting the molecular network between mRNAs, miRNAs, and TFs using robust computational biology approaches. The transcriptomic data of bronchial epithelial cells of severe asthma patients and healthy controls was studied by different systems biology approaches like differentially expressed gene detection, functional enrichment, miRNA-target gene pairing, and mRNA-miRNA-TF molecular networking. We detected the differential expression of 1703 (673 up-and 1030 down-regulated) genes and 71 (41 up-and 30 down-regulated) miRNAs in the bronchial epithelial cells of asthma patients. The DEGs were found to be enriched in key pathways like IL-17 signaling (KEGG: 04657), Th1 and Th2 cell differentiation (KEGG: 04658), and the Th17 cell differentiation (KEGG: 04659) (p-values = 0.001). The results from miRNAs-target gene pairs-transcription factors (TFs) have detected the key roles of 3 miRs (miR-181a-2-3p; miR-203a-3p; miR-335-5p), 6 TFs (TFAM, FOXO1, GFI1, IRF2, SOX9, and HLF) and 32 miRNA target genes in eliciting autoimmune reactions in bronchial epithelial cells of the respiratory tract. Through systemic implementation of comprehensive system biology tools, this study has identified key miRNAs, TFs, and miRNA target gene pairs as potential tissue-based asthma biomarkers.

Daily Physical Activity in Asthma and the Effect of Mepolizumab Therapy.

For the various asthma-specific beneficial effects of physical activity, daily physical activity (DPA) and the potential of asthma therapies on DPA require better characterization. Hence, we aimed to determine (a) the DPA of asthma patients, and (b) the effect of add-on mepolizumab on the DPA of severe asthma patients. Methods: Adult outpatients with mild-to-moderate or severe asthma had accelerometer assessment of DPA. Severe asthma patients who were commenced on mepolizumab had their DPA reassessed after 12 months. Results: For the total cohort (n = 36), daily step count, time in moderate-to-vigorous physical activity (MVPA), MVPA volume and Movement Intensity (MI) were 7806 ± 3823 steps, 123 (interquartile range, 63) min, 657 ± 255 MET·min and 1.96 (0.45) m/s2, respectively. All patients met at least one recommendation for DPA but less than half met recommendations for vigorous DPA. Patients on mepolizumab therapy increased daily step count (646 steps; 9%), time in MVPA (20 min; 21%), MVPA volume (87 MET·min; 17%) and MI (0.11 m/s2; 6%) for the same amount of moving time; lung function, asthma control and health-related quality of life also improved. Conclusions: Analysis of the first national data on DPA in asthma and novel comparison against current applicable guidelines and identified beneficial thresholds showed borderline levels of DPA with room for improvement especially for severe asthma patients. In a non-sedentary cohort of severe asthma patients, mepolizumab conferred significant and meaningful improvements in DPA.

Eosinophils promote proliferation of pulmonary structural cells by stimulating extracellular matrix production in asthma

Introduction. Eosinophilic asthma can be characterized by intense infiltration of eosinophils into the airways, where they abundantly release various cytokines, chemokines and growth factors. Airway remodeling is closely related to increased airway smooth muscle (ASM) mass; however, another important feature could be changes in extracellular matrix (ECM) homeostasis, driven by the production of ECM proteins and metalloproteinases by lung structural cells. Aim. To evaluate and compare eosinophil adhesion to ASM cells and pulmonary fibroblasts or their secreted ECM and the effect on pulmonary structural cell autocrine proliferation adjustment in asthma. Methods. A total of 12 allergic asthma (AA), 8 severe eosinophilic asthma (SEA) patients and 11 healthy subjects (HS) were examined. Blood eosinophils were isolated using high density Ficoll centrifugation and magnetic separation. For each study individual combined cell cultures (co-cultures) between isolated eosinophils and pulmonary structural cells or their secreted ECM were prepared. ECM purification was performed using ammonium hydroxide (NH4OH) based cell lysis. Eosinophils adhesion was evaluated by measuring eosinophils peroxidase activity in co-cultures; pulmonary structural cell proliferation was measured by AlamarBlue assay. Results. In all investigated groups eosinophil adhesion to ECM was significantly increased compared to eosinophil adhesion to ASM cells and pulmonary fibroblasts (p &lt; 0.01). Eosinophil adhesion to ASM cells and pulmonary fibroblasts or their secreted ECM in asthma groups was significantly enhanced compared to HS group (p &lt; 0.05). Isolated ASM cell or pulmonary fibroblast’ produced ECM after co-cultures with AA, SEA and HS eosinophils promoted newly seeded ASM cell and pulmonary fibroblast proliferation (p &lt; 0.01) with stronger effect in both asthma groups. ECM, isolated after combined cultures with AA, SEA or HS eosinophils and the blood serum of the study patient also significantly promoted the proliferation of ASM cells and pulmonary fibroblasts (p &lt; 0.01). Isolated ASM cell or pulmonary fibroblast’ produced ECM after co-cultures with AA and SEA eosinophils had a stronger effect to newly seeded pulmonary structural cell proliferation than after co-cultures with HS eosinophils. Conclusions. Eosinophils demonstrate enhanced adhesion to ECM components than to ASM cells or pulmonary fibroblasts, and adhesion further increases in asthma. Pulmonary structural cells promote their proliferation in autocrine manner via released ECM components after incubation with eosinophils in asthma.

Characterization of Patients in the International Severe Asthma Registry with High Steroid Exposure Who Did or Did Not Initiate Biologic Therapy.

BackgroundMany severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics.MethodsBaseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson’s chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons.ResultsBetween January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/µL, p=0.003), serious infections (49.0% vs 13.3%, p<0.001), nasal polyps (35.2% vs 23.6%, p<0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147).ConclusionAround one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.

NOVEL INSIGHTS GAINED FROM AN INTEGRATED ELECTRONIC INHALER IN PATIENTS WITH SEVERE ASTHMA TREATED WITH BIOLOGICS

NOVEL INSIGHTS GAINED FROM AN INTEGRATED ELECTRONIC INHALER IN PATIENTS WITH SEVERE ASTHMA TREATED WITH BIOLOGICS

LONG-TERM REAL-WORLD EFFECTIVENESS OF BENRALIZUMAB IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA: RESULTS FROM THE ZEPHYR 2 STUDY

LONG-TERM REAL-WORLD EFFECTIVENESS OF BENRALIZUMAB IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA: RESULTS FROM THE ZEPHYR 2 STUDY

Association Between Medication Adherence and Risk of COPD in Adult Asthma Patients: A Retrospective Cohort Study in Canada.

Poor adherence to prescribed asthma medications and risk of severe asthma exacerbations have been well established. However, the effects of changes in asthma medication compliance levels and subsequent risk of COPD is unknown and yet to be investigated. This study investigated the independent effect of medication adherence (MA) and asthma severity levels on the risk of COPD. We used four linked administrative health databases from the Population data BC to identify asthma patients aged 18 years and older between January 1, 1998 and December 31, 1999 without diagnosis of COPD. The primary event was time-to-COPD diagnosis during the follow-up period (January 1, 2000 to December 31, 2018). The proportion of days covered (PDC) - was used as a surrogate measure for medication adherence (MA) assessed at optimal-level (≥ 0.80), Intermediate-level (0.50-0.79), and low-level (< 0.5) of adherence. A propensity adjusted analysis with Marginal Structural Cox (MSC) model was employed to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for the effect of medication adherence and asthma severity over time. At cohort entry, the sample included 68,211 asthma patients with an overall mean age of 48.2 years. The 18-year incidence of COPD in asthma patients was 9.8 per 1000-persons year. In an inverse weighted propensity adjusted analysis of the MSC model, higher MA levels were significantly associated with decreased risk of COPD as follows: optimal-level (aHR: 0.19, 95% CI: 0.17-0.24); Intermediate-level (aHR: 0.20, 95% CI: 0.18, 0.23) compared to the low-level adherence group. A significant increase in COPD risk was observed in severe asthma patients with low medication adherence (aHR: 1.72, 95% CI: 1.52-1.93), independent of other patient factors. Optimal (≥ 0.80) and intermediate adherence (0.5 to 0.79) levels were associated with reduced risk of COPD incidence over time. Interventions aimed at improving adherence to prescribed medications in adult asthma patients should be intensified to reduce their risk of COPD.

WITHDRAWN

SESSION TITLE: Biologics and Severe Asthma: Latest Outcome Data SESSION TYPE: Original Investigations PRESENTED ON: 10/16/22 10:30 AM - 11:30 AM PURPOSE: Dupilumab which is an anti-IL-4/13 monoclonal antibody can be used to treat severe uncontrolled asthma. Since its approval, patients who were uncontrolled on other biological therapies are switched to Dupilumab. Our study aims to evaluate the efficacy and safety of switching Mepolizumab to Dupilumab for the treatment of severe asthma in a real-world severe asthma clinic in a tertiary hospital in Riyadh, Saudi Arabia. METHODS: We did a chart review on severe asthma patients who were treated with Mepolizumab for at least 6 months with suboptimal asthma control and are currently on Dupilumab for more than 6 months from January 2017 through August 2021. Multiple outcomes were observed which include the rate of asthma exacerbation (RAE), reduction in maintenance Oral Corticosteroids (mOCS) dose, improvement in Asthma Control, lung function, and effects on total IgE and eosinophils. RESULTS: A total of 14 severe asthma patients (85% females) were on mepolizumab for at least 6 months then switched to Dupilumab. The average age was 43 years with an average BMI of 31, half of the patients have a background of Chronic Rhinosinusitis with Nasal Polyposis. At baseline prior to mepolizumab, patients had an average of 18.5 Emergency Room (ER) visits and 14.5 short courses of Prednisone due to asthma exacerbations. Their average Asthma Control Test (ACT) was 10 at baseline and 57% of them were on mOCS at baseline. The average FEV1 pre-bronchodilator (BD) was 1.67 L. Eosinophils count prior to Mepolizumab was 0.77 and total IgE was 317. After a minimum of 6 months on Mepolizumab, results were as follows: both average ER visits and short courses of Prednisone for asthma attacks were reduced to 3.7 and 5 respectively. The average Asthma Control Test (ACT) improved to 13.2. All 14 patients were uncontrolled on Mepolizumab with 23.7% of them were on mOCS. Their average FEV1 was 1.86. Prior to Dupilumab, the average peripheral eosinophils was 0.23 along with 332 for total IgE. 6 months post-Dupilumab initiation, there was a significant improvement in multiple outcomes. The average RAE was 1.42 and ACT was 18.1. Only 10% of patients are on mOCS. Furthermore, the average FEV1 has also improved compared to previous results with pre FEV1 of 2.48 (82%) and the average total IgE was 156. However, eosinophils were higher compared to Mepolizumab period with an average count of 1.54 and 0.92 at 3 and 6 months period. CONCLUSIONS: In this retrospective real-life study, we have shown that switching patients who were uncontrolled on Mepolizumab to Dupilumab had a significant effect in reducing annual asthma exacerbations. It also helped in reducing daily OCS dose along with improvement in lung function and asthma symptoms. Overall, Dupilumab was a safe medication apart from an increase in eosinophils count. CLINICAL IMPLICATIONS: Dupilumab showed that it can improve severe asthmatics who failed Mepolizumab. DISCLOSURES: No relevant relationships by Riyad Al-Lehebi No relevant relationships by Yasmin Alkhunaizi No relevant relationships by SAUD ALMOUSA

Contribution of allergy in the acquisition of uncontrolled severe asthma.

Asthma is a multifactorial, heterogeneous disease that has a challenging management. It can be divided in non-allergic and allergic (usually associated with house dust mites (HDM) sensitization). There are several treatments options for asthma (corticosteroids, bronchodilators, antileukotrienes, anticholinergics,…); however, there is a subset of patients that do not respond to any of the treatments, who can display either a T2 or a non-T2 phenotype. A deeper understanding of the differential mechanisms underlying each phenotype will help to decipher the contribution of allergy to the acquisition of this uncontrolled severe phenotype. Here, we aim to elucidate the biological pathways associated to allergy in the uncontrolled severe asthmatic phenotype. To do so, twenty-three severe uncontrolled asthmatic patients both with and without HDM-allergy were recruited from Hospital Universitario de Gran Canaria Dr. Negrin. A metabolomic fingerprint was obtained through liquid chromatography coupled to mass spectrometry, and identified metabolites were associated with their pathways. 9/23 patients had uncontrolled HDM-allergic asthma (UCA), whereas 14 had uncontrolled, non-allergic asthma (UCNA). 7/14 (50%) of the UCNA patients had Aspirin Exacerbated Respiratory Disease. There were no significant differences regarding gender or body mass index; but there were significant differences in age and onset age, which were higher in UCNA patients; and in total IgE, which was higher in UCA. The metabolic fingerprint revealed that 103 features were significantly different between UCNA and UCA (p < 0.05), with 97 being increased in UCA and 6 being decreased. We identified lysophosphocholines (LPC) 18:2, 18:3 and 20:4 (increased in UCA patients); and deoxycholic acid and palmitoleoylcarnitine (decreased in UCA). These metabolites were related with a higher activation of phospholipase A2 (PLA2) and other phospholipid metabolism pathways. Our results show that allergy induces the activation of specific inflammatory pathways, such as the PLA2 pathway, which supports its role in the development of an uncontrolled asthma phenotype. There are also clinical differences, such as higher levels of IgE and earlier onset ages for the allergic asthmatic group, as expected. These results provide evidences to better understand the contribution of allergy to the establishment of a severe uncontrolled phenotype.

Narrative review to capture patients' perceptions and opinions about non-response and response to biological therapy for severe asthma.

There are now many biological therapies to treat severe asthma. To assess which work best for which patient, we need to develop definitions of response. This narrative review aims to capture severe asthma patients' perceptions about non-response and response to biological therapy. Four bibliographic databases were searched from inception to September 2021. Grey literature was searched with the involvement of patient representatives. A thematic approach was used for synthesis. No qualitative studies specifically explore patients' perspectives on response to biological therapy for severe asthma. Three papers and one published asthma patient interview were included. Relevant grey literature was included from online discussion forums, blogs and social media websites. Adult patients framed positive response to biological therapy in terms of reduced burden of disease and treatment. Both were multifaceted. Some patients experienced reduced benefit from biological therapy over time. There was a group of patients who described a limited response or non-response to biological therapy. This was framed within the context of continuing hospitalisation and oral corticosteroid treatment. The speed of onset of benefit was felt to be important by some. Definitions of non-response and response need to be patient-centred, yet there is a complete lack of qualitative research focused on this topic. By combining relevant published and grey literature we have provided a description of adult patients' perceptions of response to biological therapy in severe asthma. We now need to understand the views of children and adolescents with severe asthma and their carers, and diverse patient experiences in real-world settings.

Guidance for Administering Biologics for Severe Asthma and Allergic Conditions.

Asthma is a common respiratory disorder in Canada for which biologics may be prescribed for poorly controlled illness. Treatment with biologics, however, is sometimes inappropriately discontinued due to misconceptions regarding their potential immunologic effects, and concerns surrounding their continued use in severe asthma during the COVID-19 pandemic continue to propagate. Biologics can still be administered in a majority of health and treatment conditions. With regard to cardiac-related issues such as hypertension or cardiovascular disease (CVD), there is no solid evidence that suggests biologics should be withheld, as the benefits of treatment outweigh the risks. Asthmatic patients on biologic treatment should also continue treatment if they have, or are currently being treated for, a respiratory infection, including COVID-19. Evidence also indicates the importance of maintaining asthma control to reduce the risk of severe COVID-19 infection. Biologic treatment can be administered in severe asthmatic patients with bronchiectasis, though further evidence is needed to better understand the benefits. Biologic treatment should be continued postsurgery to reduce postoperative respiratory complications, as well as throughout the course of pregnancy. Regarding concerns over vaccine administration, nearly all vaccines can be given without interruption of biologic treatment in patients with severe asthma or allergic conditions. Appropriate screening for respiratory illnesses, such as COVID-19, continues to be warranted in clinical practices to reduce the risk of transmission. As recommendations from public health and regulatory agencies have been lacking, this guidance document addresses the administration of biologics in different health circumstances and respiratory illness screening during the COVID-19 pandemic.