Eosinophils are a subset of granulocytes that protect the host against fungal and parasitic infection through secretion of their granular contents. In response to specific stimuli, eosinophils also undergo a type of lytic cell death, referred to as eosinophil extracellular trap (EET)-associated cell death (EETosis), where histone citrullination facilitates chromatin decondensation, cell rupture and release of pro-inflammatory, decondensed chromatin into the extracellular environment as EETs. In this study, we show the abundant presence of eosinophils and citrullinated histones in nasal polyp tissue of patients with eosinophilic chronic rhinosinusitis (ECRS). Using live imaging microscopy on purified human eosinophils, we demonstrate that physiologically relevant stimuli induce release of citrullinated EETs and the marker of eosinophil activation galectin-10. While the kinetics of release of EETs and galectin-10 are similar, inhibitors of citrullination block EETosis in a dose dependent manner but fail to inhibit galectin-10 release. The importance of citrullination is further exemplified with CIT-013, a monoclonal antibody specific for citrullinated histones H2A and H4. CIT-013 potently inhibits release of EETs (half-maximal inhibitory concentration of 2.5 nM) without inhibiting other eosinophil functions such as degranulation, adhesion, superoxide production and induction of chemokine expression. Together, this study provides new insights into the requirement of protein arginine deiminase 4 (PAD4) for EETosis, differentiates requirements of EETosis from galectin-10 release, and identifies a novel therapeutic approach for EETosis inhibition by targeting citrullinated histones in eosinophil-driven diseases such as ECRS.

Background: Prior studies have demonstrated associations between eosinophil activation products and incident stroke. We sought to investigate associations between blood eosinophil count and imaging markers of atherosclerosis (carotid artery plaque [CAP] and coronary artery calcium [CAC]) in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: The MESA enrolled adults aged 45-84 years, free of atherosclerotic cardiovascular disease (ASCVD) at baseline. ASCVD risk factors, blood eosinophils, CAP presence and score (0-12) and CAC presence and Agatston score were measured at exam 5. Logistic and linear regression models were employed to test the association of blood eosinophils, CAP and CAC presence and score (log[score+1]) adjusted for biologic confounders. Results: The 2,166 participants were a mean (standard deviation [SD]) 69.6 (9.3) years old, 53% female, 29% Hispanic, 28% Black, 1% Chinese. The median (interquartile range) eosinophil count was 0.1 (0.1, 0.2)x10E3/uL, CAP score= 2 (0,4) and CAC score= 45 (0, 292) Agatston units. In risk-factor adjusted models (Table 1; model 5), increased blood eosinophil count (per 1 SD [0.15 x10E3/uL]) was associated with CAP (β = 0.05 [95% CI 0.02-0.08, p = 0.001) and CAC (β = 0.11, [95% CI: 0.01-0.21], p = 0.03) score. Similar associations were seen with eosinophils and CAP (Odds ratio [OR] = 1.12, [95% CI: 1.01-1.25], p = 0.03) and CAC (OR = 1.15, [95% CI: 1.02-1.30], p = 0.02) presence. Conclusions: In a large, contemporary, multiethnic, U.S. cohort, blood eosinophils were strongly associated with imaging measures of atherosclerosis even after adjustment for ASCVD risk factors. These data suggest potential roles of T2/eosinophilic inflammation in atherosclerosis.

Rationale: Clinical trials for severe asthma often exclude or underrepresent key patient populations. The PASSAGE study (NCT05329194) aims to assess the effectiveness and safety of tezepelumab in a diverse, real-world population of patients with severe asthma in the USA. Methods: PASSAGE is an ongoing, phase 4, multicenter, single-arm, open-label study of patients (≥12 years) with severe asthma with ≥2 exacerbations in the previous year. The study includes patients with asthma phenotypes defined by blood eosinophil counts (BECs; ≥/<300 cells/µL) and allergy status (with or without any perennial aeroallergen sensitization) at baseline. Four underrepresented populations are being assessed: Black/African American patients, adolescents (12-17 years old), patients with comorbid mild to moderate COPD and smokers (≥10 pack-years). Patients are receiving tezepelumab 210 mg subcutaneously every 4 weeks for 52 weeks (last dose: week 48). This interim analysis assessed annualized asthma exacerbation rates (AAERs) in the 12-month baseline and follow-up periods, and pre-bronchodilator forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire-6 (ACQ-6), Asthma Impairment and Risk Questionnaire (AIRQ) and St George's Respiratory Questionnaire (SGRQ) scores at baseline, weeks 24 and 52. Results: Of 208 patients included, 41% had BECs ≥300 cells/µL and 56% had confirmed allergy at baseline. Among underrepresented groups, 17% were Black/African American, 5% were adolescents, 13% had comorbid COPD and 23% were smokers. Overall, the AAER decreased by 76% (95% CI: 69, 81; baseline period: 2.96; follow-up period: 0.71); comparable reductions were observed across asthma phenotypes and underrepresented groups (Figure). At baseline, the mean (standard deviation) pre-BD FEV1 was 2.2 L (0.8 L); least-squares mean change from baseline was 0.11 L (95% CI: 0.06, 0.17) at week 24 and 0.15 L (95% CI: 0.10, 0.21) at week 52 (Figure). Among patients with a pre-bronchodilator FEV1 ≤80% predicted at baseline, least-squares mean change in pre-BD FEV1 was 0.19 L (95% CI: 0.12, 0.25) and 0.23 L (95% CI: 0.15, 0.30) at weeks 24 and 52, respectively (Figure). Clinically meaningful improvements from baseline were observed in ACQ-6, AIRQ and SGRQ scores during follow-up in 72%, 65% and 84% of patients (n=185), respectively, at week 24 and 77%, 62% and 83% (n=105), respectively, at week 52 (Figure). Conclusions: The PASSAGE interim analysis results of US patients with severe asthma treated with tezepelumab provide evidence of substantial reductions in AAERs across asthma phenotypes and underrepresented groups, with improvements in lung function, asthma control and health-related quality of life.

BACKGROUND:Chronic urticaria is a common skin condition characterized by itchy wheals (hives), angioedema, or both, lasting for 6 weeks or more. Beyond antihistamines, multiple systemic treatments are available, but there is uncertainty regarding their comparative effects on chronic urticaria outcomes. OBJECTIVE:We systematically synthesized the comparative benefits and harms of systemic treatments for chronic urticaria. METHODS:As part of updating the AAAAI/ACAAI JTFPP chronic urticaria guidelines, we searched Medline, Embase, Central, Chinese Biomedical Databases (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang from inception to February 4, 2025, for randomized trials addressing systemic immunomodulatory treatments, including phototherapy, for chronic urticaria. Paired reviewers screened records, extracted data, and assessed risk of bias. Random effects Bayesian network meta-analyses addressed urticaria activity (comprising itch and wheal scores), angioedema activity, health-related quality of life, and adverse events. The GRADE approach informed certainty-of-evidence ratings (PROSPERO: CRD42023429819). RESULTS:We included 93 studies (n = 11,398; mostly adult and adolescent participants across 83 randomized trials and 10 nonrandomized studies) that evaluated 42 interventions. With high certainty, standard-dose omalizumab (300 mg every 4 weeks) and remibrutinib are among the most effective for improving multiple patient-important outcomes. The safety profile of remibrutinib, however, is less certain. Dupilumab improved urticaria activity, but its impact on quality of life is uncertain, and no dupilumab trials addressed angioedema activity. Cyclosporine may be among the most effective for improving urticaria activity but may be among the most harmful in increasing the frequency of any adverse events. Azathioprine, dapsone, hydroxychloroquine, mycophenolate, sulfasalazine, and vitamin D may improve outcomes, while benralizumab, quilizumab, and tezepelumab may not differ from placebo, though the evidence is uncertain. Findings were consistent across age groups and baseline severity, and were robust to subgroup analyses. CONCLUSIONS:Among individuals with chronic urticaria refractory to antihistamines, standard-dose omalizumab and remibrutinib are among the most effective drugs across multiple patient-important outcomes with a favorable safety profile across the studied duration. Cyclosporine may be effective but may be among the most harmful. Dupilumab improves itch and wheals, but it is uncertain whether it improves angioedema or quality of life. Lower doses of omalizumab are of intermediate effectiveness and favorable safety. The net benefit of conventional immunosuppressants is uncertain.

Importance:Patient and caregiver values and preferences should inform clinical management. An update to the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology's Joint Task Force on Practice Parameters guidelines on chronic urticaria (CU) plans to incorporate them; however, a systematic review of evidence on the values and preferences of patients with CU and their caregivers has not been previously available. Objective:To synthesize patient and caregiver values and preferences regarding CU treatment options. Evidence Review:A systematic search was conducted of MEDLINE, Embase, PsycINFO, and CINAHL databases, from inception to May 15, 2025, for studies addressing patient and/or caregiver values and preferences for CU management. Paired reviewers independently screened studies, extracted data, and assessed risk of bias. Thematic and inductive content analysis was used to qualitatively synthesize findings and certainty of evidence was rated per the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research approach. Findings:The search resulted in 18 studies addressing the values and preferences among 28 497 participants. Moderate certainty evidence showed that patients were likely to place a high value on rapid improvement (eg, 2 days to 2 weeks) of disease signs and symptoms, long-term effectiveness, and treatments that were easy to prepare, use, and self-manage-oral or topical treatments were favored over injections, with the least favored being infusions. Low certainty evidence suggested that patients accepted minor feasibility burdens for rapid and sustained symptom relief but prioritized safety and tolerability as the risk or severity of adverse effects (eg, kidney injury, vomiting) increased. Conclusions and Relevance:This systematic review suggests that patients with CU place high value on immediate and sustained hive, itch, and swelling relief, particularly long-term symptom-free periods, but may shift to prioritizing avoiding harms and burdens as the risk and severity of adverse effects increases. These findings may serve as a resource to improve the trustworthiness of recommendations and inform future CU management and research.

Clinical trials for severe uncontrolled asthma (SUA) often underrepresent or exclude key patient populations. The phase 4 PASSAGE study assesses the effectiveness and safety of tezepelumab in a diverse, real-world US population of patients with SUA. PASSAGE is an ongoing, multicenter, single-arm, open-label study of patients (≥ 12 years) with SUA. The study enrolled participants across asthma phenotypes, based on blood eosinophil counts (BECs) (≥/< 300 cells/µL) and perennial aeroallergen sensitization, and underrepresented subgroups (Black/African Americans, adolescents, participants with comorbid mild to moderate chronic obstructive pulmonary disease (COPD) and smokers [≥ 10 pack-years]). Participants receive tezepelumab 210 mg subcutaneously every 4 weeks for 52 weeks. This interim analysis assessed annualized asthma exacerbation rates (AAERs) in the 12-month baseline period (before starting tezepelumab) and the treatment period, and changes from baseline to week 24 in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire-6 (ACQ-6) score and health-related quality of life (HRQoL) outcomes. Of 208 participants in this analysis, 41

The impact of leukotriene receptor antagonists (LTRAs) as an add-on therapy for the management of antihistamine refractory chronic urticaria (CU) is uncertain. We systematically reviewed and meta-analyzed the use of add-on LTRAs in patients with antihistamine refractory CU. We searched MEDLINE, Embase, CENTRAL, ICTRP, CBM, CNKI, VIP, and Wanfang to March 12th, 2023 for randomized controlled trials (RCTs) evaluating LTRAs as an add-on to antihistamines in antihistamine refractory CU patients. We performed random effects meta-analyses addressing urticaria severity (UAS7; 0–42; lower better), health-related quality of life (DLQI; 0 to 30; lower better), adverse events (AEs), and serious adverse events (SAEs). We used the GRADE approach to evaluate the certainty of the evidence. We identified 3,364 citations and ultimately included 7 RCTs representing 497 participants with median age of 43 years and median baseline UAS7 of 26.02 points. Compared to antihistamines alone, the addition of LTRAs improve urticaria severity (mean difference [MD] -5.99, 95%CI -9.88 to -2.10, 7 RCTs, high certainty) and may improve quality of life (MD -4.08, 95%CI -5.91 to -2.25, 1 RCT, low certainty). The impact of LTRAs on AEs (risk ratio [RR] 0.62, 95%CI 0.19 to 1.96, 3 RCTs, very low certainty) and SAEs (RR 1.02, 95%CI 0.02 to 50.41, 1 RCT, very low certainty) was uncertain. Add-on LTRAs reduce urticaria severity in antihistamine refractory CU patients, however, further research is needed to evaluate its harms in this population.

BACKGROUND:Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE:To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS:We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS:We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS:Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult. In this regard, multicenter retrospective collaborative studies focusing on disease manifestations and treatment responses in rare EADs have provided invaluable data for physicians managing patients with these conditions and helped identify important questions for future translational research. During the Clinical Pre-Meeting Workshop held in association with the July 2023 biennial meeting of the International Eosinophil Society in Hamilton, Ontario, Canada, the successes and limitations of pivotal multicenter retrospective studies in EADs were summarized and unmet needs regarding the establishment of guidelines for use of biologics in rare EADs were discussed. Key topics of interest included (1) clinical outcome measures, (2) minimally invasive biomarkers of disease activity, (3) predictors of response to biologic agents, and (4) long-term safety of eosinophil depletion. Herein, we report a summary of these discussions, presenting a state-of-the-art overview of data currently available for each of these topics, the limitations of the data, and avenues for future data generation through implementation of multidisciplinary and multicenter studies.

BACKGROUND:Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, chronic inflammatory disease characterized by asthma and small/medium vessel vasculitis. Mepolizumab is approved for use in EGPA disease management alongside oral corticosteroids (OCS), but evidence of its real-world impact is limited. OBJECTIVE:To compare real-world treatment patterns and health outcomes, particularly OCS use, EGPA-related hospitalizations/relapses, and asthma exacerbations pre- and post-mepolizumab initiation in US patients with EGPA. METHODS:Patients with EGPA receiving more than or equal to 2 mepolizumab doses were identified using administrative claims data from Komodo Health's Comprehensive Dataset (between December 2016-March 2020). Outcomes assessed pre- and post-mepolizumab initiation included corticosteroid/other medication use, EGPA-related hospitalizations/relapses, and asthma exacerbations. RESULTS:Overall, 114 patients were identified; of these, 60 (53%) received mepolizumab 300 mg at index. Average daily OCS dose per dispensing was significantly lower post- vs pre-mepolizumab initiation (21.2 vs 26.8 mg/d, 21% relative reduction, P < .001); mean number of OCS bursts also decreased (0.9 vs 1.8, 50% relative reduction, P < .001). Patients experienced significantly lower rates of EGPA-related hospitalization (0.86 vs 1.55 per-person year [PPY], 49% relative reduction, P = .004) and EGPA relapse (3.18 vs 3.94 PPY, 19% relative reduction, P = .004) post- vs pre-initiation. Most patients (91%) had an asthma diagnosis at baseline; among these patients, asthma exacerbation rates were significantly lower post- vs pre-initiation (1.05 vs 1.84 PPY, 42% relative reduction, P = .004). CONCLUSION:Mepolizumab was associated with significant steroid-sparing benefits and significantly reduced rates of EGPA-related hospitalizations, EGPA relapses, and asthma exacerbations in this real-world study of US patients with EGPA, confirming the benefits of mepolizumab treatment seen in clinical trials.

Abstract Background Patients with asthma with an eosinophilic phenotype may be eligible for additional treatment options to improve disease control; however, the prevalence and frequency of eosinophil testing is unknown. This study assessed blood eosinophil count testing prevalence in patients with asthma by exacerbation frequency and healthcare provider (HCP) type. Methods This was a retrospective, longitudinal, real-world study (GSK ID: 214470) utilizing the Merative Explorys® Universe electronic health records database. Eligible patients had ≥ 2 asthma diagnostic codes (January 2016–December 2018) (Index date: first asthma diagnosis). Outcomes included patient demographics and clinical characteristics (12 months pre-index [baseline]), and prevalence of blood eosinophil count testing, stratified by exacerbation frequency (infrequent exacerbations [< 2]) or frequent exacerbations [≥ 2] or primary HCP (Allergist/Pulmonologist, a primary care physician [PCP] or other HCP) during the 12 months post-index (follow-up). Results Of 400,254 patients included (mean age: 51.2 years; 70.8% female), the most common provider type at baseline was a PCP (76.8%). A higher proportion of patients with frequent exacerbations had blood eosinophil count tests at baseline (55.4–69.5%) and follow-up (67.9–75.1%), compared with patients with infrequent exacerbations (55.5–63.7%, 62.4–67.3%). Significantly more patients in the Allergist/Pulmonologist subgroup had ≥ 1 blood eosinophil count test result compared with patients in the PCP subgroup at both baseline (59.9% vs. 50.7%; p < 0.001) and follow-up (59.0% vs. 56.2%; p < 0.001). In the total population, the mean (SD) number of tests ordered was 3.4 (5.3) and 4.1 (6.4) during the baseline and follow-up periods, respectively. A greater mean number of tests were ordered for patients with frequent exacerbations, most apparently in the Allergist/Pulmonologist subgroup during baseline and follow-up (7.4 vs. 4.9). For patients with frequent exacerbations and blood eosinophil count test results, the mean (SD) number of tests ranged from 3.1 (4.6) to 5.8 (8.3) at baseline and 5.1 (8.5) to 7.4 (10.6) during follow-up. Conclusions The prevalence of blood eosinophil count testing in patients with asthma remains suboptimal. Routine blood eosinophil count testing should be considered by HCPs for patients with asthma to increase identification of the eosinophilic asthma phenotype, which may inform the decision to advance to targeted biologic therapy.

BACKGROUND:Topical corticosteroids are widely used as a treatment for itch and wheals (urticaria), but their benefits and harms are unclear. OBJECTIVE:To systematically synthesize the benefits and harms of topical corticosteroids for the treatment of urticaria. METHODS:We searched MEDLINE, EMBASE, and CENTRAL from database inception to March 23, 2024, for randomized trials comparing topical corticosteroids with placebo for patients with urticaria (either chronic spontaneous or inducible urticaria or acute urticaria elicited from skin/intradermal allergy testing). Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects meta-analyses addressed urticaria severity, itch severity (numeric rating scale; range 0-10; higher is worse), and adverse events. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty of evidence ratings. PROSPERO registration: CRD42023455182. RESULTS:A total of 19 randomized controlled trials enrolled 379 participants with a median of mean age of 30.1 (range 21.1-44.0) years. Compared with placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95% CI 0.38-0.59; low certainty) and itch severity (mean difference -1.30, 95% CI -5.07 to 2.46; very low certainty). Topical corticosteroids result in little to no difference in overall adverse events (94 fewer patients per 1000, 95% credible intervals 172 fewer to 12 more; high certainty). CONCLUSION:Compared with placebo, topical corticosteroids may result in a reduction of wheal size and little to no difference in overall adverse events. Topical corticosteroids may reduce itch severity, but the evidence is very uncertain. Future large, randomized trials addressing the use of topical corticosteroids would further support optimal urticaria management.