Praveen Akuthota

Background: Inhaled corticosteroid (ICS)-containing reliever therapy has demonstrated efficacy in improving asthma outcomes when compared to short-acting beta2-agonists (SABA) alone but remains underutilized. The purpose of this guideline is to provide recommendations surrounding the use of combination ICS-formoterol or ICS+SABA (in combination or separate inhalers) as reliever therapy across the asthma severity spectrum in adolescents and adults. Methods: The American Thoracic Society clinical practice guideline panel evaluated six research questions in the PICO format addressing the use of ICS-containing reliever therapy across National Asthma Education and Prevention Program (NAEPP) asthma treatment steps 1-5. The methodology team conducted systematic literature reviews and GRADE assessments, which the panel utilized to inform the recommendations for each specific PICO and overall. Recommendations: In patients at NAEPP steps 1 and 2, the panel made strong recommendations for the use of as-needed-only ICS-SABA or ICS-formoterol over SABA-only therapy, and conditional recommendations over scheduled ICS + as-needed SABA. In patients at NAEPP steps 3-5, the taskforce made a strong recommendation for the use of maintenance-and-reliever therapy (MART) with ICS-formoterol over scheduled ICS-LABA plus as-needed SABA. In patients at NAEPP steps 3-5 who are using scheduled maintenance ICS-LABA, the panel made a conditional recommendation for use of ICS+SABA reliever over SABA reliever. In considering these recommendations, the panel valued the importance of preventing severe exacerbations and considered the risk of SABA-only treatment, as well as ICS and systemic corticosteroid (SCS) exposure. Conclusions: This clinical practice guideline, informed by systematic reviews and GRADE-based appraisals of PICO-framed evidence, makes these evidence-based recommendations for the safe and effective use of ICS-containing reliever therapy in asthma.

Background: Rademikibart, an IL‐4Rα‐targeting antibody, demonstrated efficacy in a Phase 2b trial of adults with moderate‐to‐severe uncontrolled asthma (NCT04773678). We report exploratory and predominantly post hoc subgroup analyses, according to baseline eosinophil count (EOS) and fractional exhaled nitric oxide (FeNO). Methods: Patients were randomized, double‐blind, to rademikibart 150 mg or 300 mg Q2W (600‐mg loading) or placebo, with medium‐to‐high dose inhaled corticosteroids and ≥ 1 reliever/controller. Up to eight EOS/FeNO subgroups were investigated, focusing on the following five: ≥ 300 cells/μL and ≥ 25 ppb ( N = 80); ≥ 25 ppb ( N = 142); ≥ 300 cells/μL ( N = 129); ≥ 150 cells/μL ( N = 247); 150– < 300 cells/μL ( N = 118). Results: Prebronchodilator FEV ₁ increased significantly at first assessment (Week 1) and was sustained throughout the 24‐week treatment period. FEV ₁ and asthma control (ACQ‐6) improvements were greatest when baseline EOS and FeNO were both elevated. At Week 1, after a 600‐mg loading dose, placebo‐adjusted FEV ₁ increased by 422 mL (≥ 300 cells/μL and ≥ 25 ppb), 339 mL (≥ 25 ppb), 324 mL (≥ 300 cells/μL), 227 mL (≥ 150 cells/μL), and 141 mL (150– < 300 cells/μL). At Week 24, with 300 mg Q2W, placebo‐adjusted FEV ₁ increased by 519 mL (≥ 300 cells/μL and ≥ 25 ppb), 401 mL (≥ 25 ppb), 394 mL (≥ 300 cells/μL), 287 mL (≥ 150 cells/μL), and 159 mL (150– < 300 cells/μL). Exacerbations decreased by ≥ 63% per subgroup. Rademikibart was well tolerated. No eosinophilia (Preferred Term) was reported. Grade 1 eosinophil count increased did not lead to treatment discontinuation ( n = 2). Conclusions: Rapid and sustained improvements were more pronounced in patients with type 2‐high biomarkers than previously reported in the overall study population.

E-cigarette use has become widespread, and its effects on airway inflammation and disease are not fully delineated. E-cigarette vapor extract (EVE) profoundly affects neutrophil function. We hypothesized that EVE also alters eosinophil function and thus could impact allergic airways disease. We employed RNA-sequencing to measure the ex vivo effect of EVE components on human eosinophil transcription. Blood eosinophils from 9 non-vaping subjects without asthma were isolated by negative selection. Cells were incubated for 48 hours with EVE consisting of glycerin, propylene glycol and nicotine (EVE+), EVE without nicotine (“EVE-”), air-exposed media termed Extract Buffer (EB), or untreated media. Bulk RNA-sequencing was performed. Transcriptomic analysis revealed that the EB, EVE-, and EVE+ conditions showed highly variable gene expression with respect to No Treatment and each other. Differential gene expression analysis comparing a combination of EVE+, EVE-, and EB revealed 3,030 differentially expressed genes (DEG) with adjusted p value < 0.05 and log2 fold change >0.5 or <0.5. There were 645 DEG between EB and EVE-, 1,713 between EB and EVE+, and 404 between EVE- and EVE+. Gene set enrichment analysis demonstrated that DEG between both EVE+ and EVE- and the EB control were positively enriched for heme metabolism and apoptosis and negatively enriched TNFα signaling, IFNγ signaling, and inflammatory response. Thus, EVE significantly alters eosinophil metabolic and inflammatory pathways, mediated by propylene glycol and glycerin with both enhancing and unique effects of nicotine. This study motivates further research into the pathogenic effects of vaping on airway eosinophils and allergic airways disease.

Background: The Mepolizumab in Relapsing or Refractory EGPA (MIRRA) trial (GSK ID: 115921/NCT02020889) demonstrated that mepolizumab increased remission time and reduced oral corticosteroid (OCS) use compared with placebo in patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA). The present analysis investigated the impact of baseline characteristics on clinical outcomes and characterised the OCS-sparing effect of mepolizumab.Methods: In a phase 3, randomised controlled trial for patients with EGPA (MIRRA), patients received standard of care plus mepolizumab 300 mg or placebo every 4 weeks for 52 weeks. The accrued duration of remission, the proportion of patients in remission at weeks 36 and 48, and the proportion of patients with clinical benefit (remission, OCS or relapse-related) were assessed according to baseline EGPA characteristic subgroups (post hoc). Mepolizumab-related OCS-sparing benefits were also quantified.Results: Accrued duration of remission and the proportion of patients in remission at weeks 36 and 48 were greater with mepolizumab than placebo across the baseline subgroups of refractory disease, immunosuppressant use, EGPA duration, relapse number and OCS use ≤20 mg·day⁻¹. The proportion of patients with clinical benefit was greater with mepolizumabversusplacebo (range 76–81%versus25–39%), irrespective of immunosuppressant use or EGPA duration. Patients treated with mepolizumabversusplacebo accrued significantly more weeks on OCS ≤4 mg·day⁻¹(OR 5.06, 95% CI 2.47–10.38) and had a mean of 1423.1 mg less per-patient OCS exposure over 52 weeks.Conclusions: Mepolizumab treatment provided benefits to patients with EGPA across varying baseline clinical characteristics and can be considered an OCS-sparing treatment in EGPA.

Asthma exacerbations occur in the context of a complex interplay between external exposures and host factors. Respiratory tract viral infections, in particular rhinovirus, are dominant initiators of exacerbations, with allergens and other inhalation exposures as additional key contributors. The presence of underlying type II inflammation, with associated biomarker elevations, is a major driver of exacerbation risk and mechanism, as evidenced by the consistent reduction of exacerbations seen with biologics targeting these pathways. Several genetic polymorphisms are associated with exacerbations, and while they may individually have small effects, they are cumulatively important and magnified by environmental exposures. A history of exacerbations predicts future exacerbations with potentially negative implications on long-term lung health. Keywords Exacerbations Respiratory virus Infection Exposures Rhinovirus COVID Allergens Anti-viral immunity Remodeling Heterogeneity Allergens Environmental exposures

Objective: To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype.Methods: The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or less mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino‐nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed.Results: A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission.Conclusion: Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype.