Eosinophilic Asthma Research Articles

Benralizumab in Severe Eosinophilic Asthma and Chronic Rhinosinusitis with Nasal Polyps: The Real-World, Multi-Country RANS Observational Study.

Real-world evidence of benralizumab effectiveness on nasal polyps (NP) and asthma outcomes in patients with severe eosinophilic asthma (SEA) and comorbid chronic rhinosinusitis with NP are limited. The objective of this study was to assess NP and asthma outcomes in benralizumab-treated patients with SEA and comorbid NP in a real-world setting. RANS was a retrospective, multi-country observational study (ClinicalTrials.gov: NCT05180357) using medical chart reviews of adults with SEA and comorbid NP. Total NP Score (NPS), SinoNasal Outcome Test-22 (SNOT-22) total score, annualized exacerbation rate (AER), and 6-item Asthma Control Questionnaire (ACQ-6) and Asthma Control Test (ACT) scores during the 12 months pre-index (baseline) and post-index (follow-up) were measured. Clinically meaningful improvement from baseline following treatment, in terms of total NPS (≥1-point reduction), SNOT-22 total (≥8.9-point reduction), ACQ-6 (≥0.5-point reduction) or ACT (≥3-point increase) scores, were reported. A total of 233 patients were included. Baseline mean (standard deviation [SD]) NPS and SNOT-22 total scores were 3.8 (2.4) and 47.5 (22.6), respectively. The mean change (95% confidence interval [CI]) from baseline was -1.2 (-1.7, -0.6) for NPS, and -19.8 (-23.6, -15.9) for SNOT-22. The AER (95% CI) was 1.2 (0.96, 1.41) at baseline and 0.2 (0.13, 0.28) at follow-up. Mean (SD) ACQ-6 and ACT scores were 1.6 (1.3) and 15.0 (5.2) at baseline and 0.8 (1.0) and 22.0 (3.9) at follow-up, respectively. The proportion of patients who achieved clinically meaningful improvements in NPS, SNOT-22 total, ACQ-6, and ACT scores was 49.1%, 67.6%, 56.6%, and 81.1%, respectively. In this real-world study, improvements in NP and asthma outcomes in patients with SEA and comorbid NP were observed during the 12 months following benralizumab initiation.

Role of Mepolizumab in COVID Patients with Severe Eosinophilic Asthma

Aim: To evaluate the effect of Mepolizumab on COVID-19 patients with severe eosinophilic asthma and other comorbidities.

Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology

Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death invitro and invivo. Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

Asthma loss of control after switch from anti-IL-5/5R drugs to dupilumab in severe eosinophilic asthma: A case series

Asthma loss of control after switch from anti-IL-5/5R drugs to dupilumab in severe eosinophilic asthma: A case series

Eosinophilic esophagitis and comorbid pathology: current state of the problem

Eosinophilic esophagitis and asthma are often found as part of comorbid pathology in children and adults, along with other manifestations of atopy. The two diseases share similar pathophysiology due to T-helper type 2 responses, common treatment approaches such as the use of glucocorticosteroids and targeted anti-cytokine biologic therapy. Patients with eosinophilic esophagitis, as with asthma, often have elevated serum markers of atopy, including IgE levels, peripheral eosinophil counts, and T-helper type 2-associated cytokines. A review of the literature shows that the true incidence of eosinophilic esophagitis remains poorly understood due to the difficulty of diagnosing this pathology, which has a mask of gastroesophageal reflux disease. Gastroesophageal reflux disease has been shown to influence asthma through microaspiration, airway hyperresponsiveness, and increased vagal tone. Understanding the relationship between gastroesophageal reflux and eosinophilic esophagitis is also being actively explored. Many works show the high efficacy of PPIs in the initial treatment of eosinophilic esophagitis and gastroesophageal reflux disease. The development of new clinical diagnostic criteria for eosinophilic esophagitis will improve the differential diagnosis of this disease and the improvement of therapeutic strategies for managing this pathology, especially in combination with asthma.

Real-world clinical remission of severe asthma with benralizumab in Spanish adults with severe asthma

Objective Patients with severe eosinophilic asthma experience high risk of exacerbations and reduced quality of life. Benralizumab, a monoclonal antibody binding to IL-5 receptor α subunit, is an approved drug for its treatment. The objective was to describe clinical remission after benralizumab prescription in routine clinical practice. Methods Retrospective multicenter study with data from four hospitals in Valencian Community (Spain) with asthma units between 2019 and 2020. Data was gathered at baseline and after 12 months. We considered clinical remission after 1 year if the patient remained without exacerbations and use of systemic corticosteroids and with good clinical control and normal lung function. Results Data from 139 patients was gathered. At the 12-month follow-up, 44.1% were in clinical remission, since 84.0%, 77.5%, 51.0% and 95.5% of patients did not experience exacerbations, had total asthma control test score of ≥20, prebronchodilator FEV1 of ≥80% and did not use systemic corticosteroids. A significant reduction of long-acting muscarinic antagonists (p = 0.0001), leukotriene receptor antagonists (p = 0.0326), oral corticosteroids (p < 0.0001) and short-acting beta agonists (p = 0.0499) was observed. Baseline factors with greatest individual influence on clinical remission were employment situation, tobacco use, comorbidity number, eosinophil value, number of exacerbations, FEV1, emergency visit number, and ACT, MiniAQLQ and TAI scores. Final analysis of multiple logistic regression indicated that having baseline FEV1 value below 80% increases remission chance 9.7 times a year compared to FEV1 >80%. Conclusion Clinical remission after treatment with benralizumab is achievable in a high percentage of patients with severe asthma eosinophilia not controlled in real life.

Mepolizumab and benralizumab in patients with severe asthma and a history of eosinophilic granulomatosis with polyangiitis.

Asthma associated with eosinophilic granulomatosis with polyangiitis (EGPA) is often severe and corticosteroid-dependent, leading to significant morbidity. Mepolizumab and benralizumab are humanized monoclonal antibodies targeting interleukin 5 (IL-5) and its receptor, respectively. They have been shown to be effective in steroid-sparing in patients with severe eosinophilic asthma. Our aim was to evaluate the efficacy and safety of mepolizumab and benralizumab prescribed for severe asthma in patients with EGPA under "real-world" conditions. This was a retrospective analysis of patients with EGPA and persistent asthma who received either mepolizumab 100 or 300 mg administered every 4 weeks, or benralizumab 30 mg administered every 4 weeks for the initial 3 injections and followed by an injection every 8 weeks thereafter, whilst combined with oral glucocorticoids. The follow-up every 6 ± 3 months included an assessment of clinical manifestations, pulmonary function tests and eosinophil cell count. The primary outcome was the proportion of patients at 12 months receiving a daily oral dose of prednisone or equivalent of 4 mg or less with a BVAS of 0. Twenty-six patients were included. After 12 months of treatment with mepolizumab or benralizumab, 32% of patients met the primary outcome and were receiving less than 4 mg of prednisone per day with a BVAS of 0. The median dose of prednisone was 10 mg per day at baseline, 9 mg at 6 months, and 5 mg at 12 months (p ≤ 0.01). At 12 months, 23% of patients were weaned off corticosteroids, while an increase or no change in dose was observed in 27% of patients. The median eosinophil count was significantly reduced from 365 cells/mm3 to 55 cells/mm3 at 6 months and 70 cells/mm3 at 12 months, respectively. No significant change was observed in FEV1. After 12 months of treatment, 14% of patients had had an average of 1 exacerbation of asthma, compared with 52% of patients before baseline. The tolerability profile was favorable. In this real-world study in patients with severe asthma and a history of EGPA asthma, mepolizumab and benralizumab had a significant steroid-sparing effect and reduced asthma exacerbation, but no significant effect on lung function.

Abstract 3412: Benralizumab for treatment of eosinophil-related cutaneous adverse events associated with checkpoint inhibitors and anticancer targeted therapies: Phase 2 study

Abstract Background: Eosinophil-related cutaneous adverse events (ercAEs) are common toxicities of PI3K inhibitors, antibody drug conjugates (ADCs), checkpoint inhibitors (CPIs), and targeted cancer therapies. While systemic corticosteroids are effective, their use is limited by additional toxicities and high recurrence. Benralizumab is an anti-IL-5Rα monoclonal antibody that induces eosinophil depletion via antibody-dependent cellular cytotoxicity, and is FDA-approved for severe eosinophilic asthma but has not been studied for ercAEs. Methods: We conducted a single-center, single-arm, Phase 2 trial (NCT04552288) of benralizumab in cancer patients with Grade 2/3 ercAEs from PI3K inhibitors, ADCs, CPIs or targeted therapies. Patients received benralizumab 30 mg subcutaneously every 4 weeks for 3 doses, then every 8 weeks for 3 doses. The primary endpoint was clinical response, defined as reduction in ercAE Grade to 0/1 at Week 4. Secondary endpoints included changes in quality of life, rash body surface area (BSA), cytokines and eosinophil biomarkers, as well as adverse events (AEs). Results: Forty-seven patients were enrolled, predominantly with breast (55.3%), bladder (10.6%), melanoma (10.6%), or kidney (6.4%) cancer. Baseline ercAEs were Grade 2 (48.9%) and Grade 3 (51.1%), most often from PI3K inhibitors (46.8%), CPIs (21.3%), tyrosine kinase inhibitors (8.5%) or ADCs (8.5%). Overall, 32 of 42 evaluable patients (76.2%) had clinical response by Week 4, with decreased ercAE grade (mean 2.4 to 0.9, p&amp;lt;0.0001), improved quality of life, reduced rash BSA, decreased peripheral and skin eosinophils (all p&amp;lt;0.0001), and cytokine changes. Clinical response by Week 4 was seen in all patients with ercAEs from alpelisib (PI3K inhibitor; n=18) or enfortumab vedotin (ADC; n=4); p-value for both: p&amp;lt;0.05. Mild-to-moderate mucositis, diarrhea, and xerosis were the most common AEs, all unrelated to benralizumab. Conclusions: Benralizumab demonstrated favorable safety and efficacy for Grade 2/3 ercAEs from cancer therapies, especially alpelisib and enfortumab vedotin. Larger placebo-controlled trials are warranted to confirm these preliminary findings. Citation Format: Mario E. Lacouture, Tara Maier, Alexander Pan, Anna Chen, George Dranitsaris, Neil J. Shah, Sarat Chandarlapaty, Chau Dang, Devika Gajria, Allison Gordon, Neil Iyengar, Pedram Razavi, Mark Robson, Ezra Rosen, Serena Wong, Ucalene Harris, Kwami Ketosugbo, Cindy Bravo, Manu Jain, Alina Markova. Benralizumab for treatment of eosinophil-related cutaneous adverse events associated with checkpoint inhibitors and anticancer targeted therapies: Phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3412.

Exploring Inflammatory Asthma Phenotypes: Proteomic Signatures in Serum and Induced Sputum.

Asthma drug responses may differ due to inflammatory mechanisms triggered by the immune cells in the pulmonary microenvironment. Thus, asthma phenotyping based on the local inflammatory profile may aid in treatment definition and the identification of new therapeutic targets. Here, we investigated protein profiles of induced sputum and serum from asthma patients classified into eosinophilic, neutrophilic, mixed granulocytic, and paucigranulocytic asthma, according to inflammatory phenotypes. Proteomic analyses were performed using an ultra-performance liquid chromatography (ultra-HPLC) system coupled to the Q Exactive Hybrid Quadrupole Orbitrap Mass Spectrometer. Fifty-two (52) proteins showed significant differences in induced sputum among the groups, while only 12 were altered in patients' sera. Five proteins in the induced sputum were able to discriminate all phenotypic groups, while four proteins in the serum could differentiate all except the neutrophilic from the paucigranulocytic inflammatory pattern. This is the first report on comparative proteomics of inflammatory asthma phenotypes in both sputum and serum samples. We have identified a potential five-biomarker panel that may be able to discriminate all four inflammatory phenotypes in sputum. These findings not only provide insights into potential therapeutic targets but also emphasize the potential for personalized treatment approaches in asthma management.

COVID-19 Clinical Features and Outcome in Italian Patients Treated with Biological Drugs Targeting Type 2 Inflammation.

This is a multicentric investigation involving two Italian centers that examined the clinical course of COVID-19 in patients receiving biological therapy targeting type 2 inflammation and those not receiving biologicals. Since the beginning of the COVID-19 pandemic, the management of respiratory and allergic disorders and the potential impact of biological therapy in the most severe forms has been a point of uncertainty. Our multicentric investigation aimed to compare the clinical course of COVID-19 and the impact of vaccination in an Italian cohort of patients with atopic disorders caused by a type 2 inflammation, such as eosinophilic asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). A questionnaire was given to patients coming to our outpatient clinic for the first evaluation or follow-up visit, asking for the clinical characteristics of the infection, the ongoing therapy during the infection, any relevant change, and the patient's vaccination status. We enrolled 132 atopic patients from two Italian centers; 62 patients were on biological therapy at the time of infection (omalizumab 31%, mepolizumab 26%, benralizumab 19%, and dupilumab 24%). The median age was 56 (IQR 22.8) for patients on biologicals and 48 (IQR 26.5) for those not on biologicals (p = 0.028). The two groups were comparable in terms of sex, body mass index (BMI), smoking history, and systemic oral corticosteroid use (OCS). There were no significant differences in non-biological therapy and comorbidity between the two groups. The patients not on biological therapy had a prevalence of 87% for asthma, 52% for CRSwNP, 10% for CSU, and 6% for AD. The patients on biologicals had a prevalence of 93% for asthma, 17% for CRSwNP, and 10% for CSU. In our work, we observed that mAbs targeting type 2 inflammation in patients with COVID-19 appeared to be safe, with no worsening of symptoms, prolongation of infection, or increase in hospitalizations. Between the two groups, there were no significant differences in the duration of swab positivity (p = 0.45) and duration of symptoms (p = 0.38). During COVID-19, patients on biologicals experienced a significant increase in common cold-like symptoms (p = 0.038), dyspnea (p = 0.016), and more, but not significant, asthma exacerbations, with no significant differences between the different biologicals. Regarding the vaccination status, we observed that there was an increased number of hospitalizations among unvaccinated patients in both groups, although the difference did not reach statistical significance. No patients on biologicals reported safety issues or adverse effects associated with the use of biological treatments during COVID-19. Our investigation showed that mAbs against type 2 inflammation given during Coronavirus Disease 2019 are safe and do not impact the clinical course or main outcomes. Therefore, we found no signals suggesting that anti-Th2 biological therapy should be discontinued during SARS-CoV-2 infection. Controlled studies and analysis, including data from registries and real-life studies, are required to draw firm conclusions regarding the safety or possible advantages that anti-type 2 mAbs could offer in particular clinical contexts, such as infections.

Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation

PurposeAsthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation. MethodsOvalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed. ResultsDEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX. ConclusionOur present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

Tezepelumab for Severe Asthma: One Drug Targeting Multiple Disease Pathways and Patient Types.

Asthma is a heterogeneous inflammatory disease of the airways, affecting many children, adolescents, and adults worldwide. Up to 10% of people with asthma have severe disease, associated with a higher risk of hospitalizations, greater healthcare costs, and poorer outcomes. Patients with severe asthma generally require high-dose inhaled corticosteroids and additional controller medications to achieve disease control; however, many patients remain uncontrolled despite this intensive treatment. The treatment of severe uncontrolled asthma has improved with greater understanding of asthma pathways and phenotypes as well as the advent of targeted biologic therapies. Tezepelumab, a monoclonal antibody, blocks thymic stromal lymphopoietin, an epithelial cytokine that has multifaceted effects on the initiation and persistence of asthma inflammation and pathophysiology. Unlike other biologic treatments, tezepelumab has demonstrated efficacy across severe asthma phenotypes, with the magnitude of effects varying by phenotype. Here we describe the anti-inflammatory effects and efficacy of tezepelumab across the most relevant phenotypes of severe asthma. Across clinical studies, tezepelumab reduced annualized asthma exacerbation rates versus placebo by 63-71% in eosinophilic severe asthma, by 58-68% in allergic severe asthma, by 67-71% in allergic and eosinophilic severe asthma, by 34-49% in type 2-low asthma, and by 31-41% in oral corticosteroid-dependent asthma. Furthermore, in all these asthma phenotypes, tezepelumab demonstrated higher efficacy in reducing exacerbations requiring hospitalizations or emergency department visits versus placebo. In patients with severe uncontrolled asthma, who commonly have multiple drivers of inflammation and disease, tezepelumab may modulate airway inflammation more extensively, as other available biologics block only specific downstream components of the inflammatory cascade.

Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. ClinicalTrials.gov-ID: NCT04305405.

The role of mitochondria in eosinophil function: implications for severe asthma pathogenesis.

Mitochondria are key metabolic hubs involved in cellular energy production and biosynthesis. ATP is generated primarily by glucose and fatty acid oxidation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in the mitochondria. During OXPHOS there is also production of reactive oxygen species (ROS), which are involved in the regulation of cellular function. Mitochondria are also central in the regulating cell survival and death, particularly in the intrinsic apoptosis pathway. Severe asthma is a heterogeneous disease driven by various immune mechanisms. Severe eosinophilic asthma entails a type 2 inflammatory response and peripheral and lung eosinophilia, associated with severe airflow obstruction, frequent exacerbations and poor response to treatment. Mitochondrial dysfunction and altered metabolism have been observed in airway epithelial and smooth muscle cells from patients with asthma. However, the role of mitochondria in the development of eosinophilia and eosinophil-mediated inflammation in severe asthma is unknown. In this review, we discuss the currently limited literature on the role of mitochondria in eosinophil function and how it is regulated by asthma-relevant cytokines, including interleukin (IL)-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), as well as by corticosteroid drugs. Moreover, we summarise the evidence on the role of mitochondria in the regulation of eosinophils apoptosis and eosinophil extracellular trap formation. Finally, we discuss the possible role of altered mitochondrial function in eosinophil dysfunction in severe asthma and suggest possible research avenues in order to better understand their role in disease pathogenesis, and identify novel therapeutic targets.

Sustained Effectiveness of Benralizumab in Naïve and Biologics-Experienced Severe Eosinophilic Asthma Patients: Results from the ANANKE Study.

Severe eosinophilic asthma (SEA) patients often present overlapping inflammatory features rendering them eligible for multiple biologic therapies; switching biologic treatment is a strategy adopted to optimize asthma control when patients show partial or no response to previous biologics. ANANKE is a retrospective, multicenter Italian study (NCT04272463). Here, we outline the characteristics and long-term clinical outcomes in naïve-to-biologics and biologics-experienced patients treated with benralizumab for up to 96 weeks. Bio-experienced patients were split into omalizumab and mepolizumab subsets according to the type of biologic previously used. A total of 124 (76.5%) naïve and 38 (23.5%) bio-experienced patients were evaluated at index date; 13 patients (34.2%) switched from mepolizumab, 21 patients (55.3%) switched from omalizumab, and four patients (10.5%) received both biologics. The mepolizumab subset was characterized by the longest SEA duration (median of 4.6 years), the highest prevalence of chronic rhinosinusitis with nasal polyposis (CRSwNP) (76.5%), and the greatest oral corticosteroid (OCS) daily dosage (median of 25 mg prednisone equivalent). The omalizumab group showed the highest severe annual exacerbation rate (AER) (1.70). At 96 weeks, treatment with benralizumab reduced any and severe AER by more than 87% and 94%, respectively, across all groups. Lung function was overall preserved, with major improvements observed in the mepolizumab group, which also revealed a 100% drop of the median OCS dose. Asthma Control Test (ACT) score improved in the naïve group while its increment was more variable in bio-experienced patients; among these, a marked difference was noticed between omalizumab and mepolizumab subsets (median ACT score of 23.5 and 18, respectively). Benralizumab promotes durable and profound clinical benefits in naïve and bio-experienced groups, indicating that a nearly complete depletion of eosinophils is highly beneficial in the control of SEA, independently of previous biologic use.

IL-5 antagonism reverses priming and activation of eosinophils in severe eosinophilic asthma

Eosinophils are key effector cells mediating airway inflammation and exacerbation in patients with severe eosinophilic asthma. They are present in increased number and activation state in the airway mucosa and lumen. Interleukin-5 (IL-5) is the key eosinophil growth factor that is thought to play a role in eosinophil priming and activation. However, the mechanism of these effects is still not fully understood. The anti-IL-5 antibody mepolizumab reduces eosinophil counts in the airway modestly but has a large beneficial effect on the frequency of exacerbations of severe eosinophilic asthma, suggesting that reduction in eosinophil priming and activation is of central mechanistic importance. In this study, we used the therapeutic effect of mepolizumab and single cell RNAseq to investigate the mechanism of eosinophil priming and activation by IL-5. We demonstrated that IL-5 is a dominant driver of eosinophil priming and plays multifaceted roles in eosinophil function. It enhances eosinophil responses to other stimulators of migration, survival and activation by activating PI3K, MAPK and p38 signal pathways. It also enhances the pro-fibrotic roles of eosinophils in airway remodeling via TGF-β pathway. These findings provide mechanistic understanding of eosinophil priming in severe eosinophilic asthma and the therapeutic effect of anti-IL-5 approaches in the disease.

TNF Superfamily and ILC2 Activation in Asthma.

Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.

Effect of Azithromycin on Asthma Remission in Adults With Persistent Uncontrolled Asthma: A Secondary Analysis of a Randomized, Double-Anonymized, Placebo-Controlled Trial

BackgroundAsthma remission is a potential treatment goal. Research questionDoes adding azithromycin to standard therapy in patients with persistent uncontrolled asthma induce remission compared to placebo? Study Design and MethodsThis secondary analysis used data from the AMAZES clinical trial – a double-blind placebo-controlled trial that evaluated the safety and efficacy of azithromycin on asthma exacerbations. The primary remission definition (referred to as clinical remission) was zero exacerbations and zero oral corticosteroids (OCS) during the previous six months evaluated at 12 months and Asthma Control Questionnaire (ACQ-5) ≤1 at 12 months. Secondary remission definitions included clinical remission plus lung function criteria (post-bronchodilator FEV1≥80% or post-bronchodilator FEV1≤5% decline from baseline) and complete remission (sputum eosinophils<3% plus the above criteria). Sensitivity analyses explored the robustness of primary and secondary remission definitions. The predictors of clinical remission were identified. Results335 participants (41.5% male; median [Q1, Q3] age 61.01 [51.03, 68.73] years) who completed the 12-month treatment period were included in the analysis. Twelve months treatment with azithromycin induced asthma remission in a subgroup of patients, and a significantly higher proportion in the azithromycin arm achieved both clinical remission (50.6% vs 38.9%; p=0.032) and clinical remission plus lung function criteria (50.8% vs 37.1%; p=0.029) compared with placebo. In addition, a higher proportion of the azithromycin group achieved complete remission (23% vs 13.7%; p=0.058). Sensitivity analyses supported these findings. Baseline factors such as better asthma-related quality of life and absence of OCS burst in the previous year predicted the odds of achieving clinical remission. Azithromycin induced remission in both eosinophilic and noneosinophilic asthma. InterpretationAdults with persistent symptomatic asthma achieved a higher remission rate when treated with azithromycin. Remission on treatment may be an achievable treatment target in moderate/severe asthma, and future studies should consider remission as an outcome measure.

Cost-effectiveness of mepolizumab for severe eosinophilic asthma in China

Objective To evaluate the economic value of mepolizumab as an add-on therapy to the standard of care (SoC) for patients with severe eosinophilic asthma in China. Methods A Markov model with three health conditions was constructed to calculate the incremental cost per quality-adjusted life year (QALY) in mepolizumab with SoC and SoC only groups from the perspective of the Chinese healthcare system throughout an entire lifespan. The model was populated with local costs, while efficacy parameters were obtained from the global Phase III MENSA trial and mortality was derived from two surveys. One-way and probabilistic sensitivity analyses were conducted. Additional scenario analysis was used to estimate the cost-effectiveness impact of changes in the price of mepolizumab. Results Over the lifetime treatment horizon, the incremental cost-effectiveness ratio (ICER) of mepolizumab plus SoC compared to SoC alone was $170 648.73 per QALY. Sensitivity analyses focused on these results. Scenario analysis showed that mepolizumab would require a price reduction of at least 82% to reach the current willingness-to-pay (WTP=$38 223.34/QALY) threshold. Conclusion Mepolizumab is not a cost-effective healthcare resource in China at its current pricing.

Eosinophilic Asthma: Pathophysiology and Therapeutic Horizons.

Asthma is a prevalent chronic non-communicable disease, affecting approximately 300 million people worldwide. It is characterized by significant airway inflammation, hyperresponsiveness, obstruction, and remodeling. Eosinophilic asthma, a subtype of asthma, involves the accumulation of eosinophils in the airways. These eosinophils release mediators and cytokines, contributing to severe airway inflammation and tissue damage. Emerging evidence suggests that targeting eosinophils could reduce airway remodeling and slow the progression of asthma. To achieve this, it is essential to understand the immunopathology of asthma, identify specific eosinophil-associated biomarkers, and categorize patients more accurately based on the clinical characteristics (phenotypes) and underlying pathobiological mechanisms (endotypes). This review delves into the role of eosinophils in exacerbating severe asthma, exploring various phenotypes and endotypes, as well as biomarkers. It also examines the current and emerging biological agents that target eosinophils in eosinophilic asthma. By focusing on these aspects, both researchers and clinicians can advance the development of targeted therapies to combat eosinophilic pathology in severe asthma.