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Introduction:Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis defined by asthma, hypereosinophilia, and multiorgan involvement. Differentiating EGPA from other eosinophilic disorders is crucial because management differs substantially. The aim of the study is to summarize the pathogenesis, epidemiology, genetics, clinical manifestation, and treatment of EGPA and to provide a comparative differential diagnosis of eosinophilic disorders.Material and Methods:Narrative review using the 2022 American College of Rheumatology (ACR)/Euro­pean Alliance of Associations for Rheumatology (EULAR) classification criteria, 2024 EULAR re­com­mendations, pivotal randomized trials, and major consensus statements; search strategy and selection criteria are detailed in the Introduction.Results:Eosinophilic granulomatosis with polyangiitis comprises 2 immunologic endotypes – anti- neutrophil cytoplasmic antibody (ANCA)-positive and ANCA-negative – with distinct organ tropism and therapeutic implications. The interleukin-5 (IL-5)–eosinophil axis is central, supporting anti-IL-5/IL-5R biologics in relapsing or refractory disease. A structured differential first excludes secondary hypereosinophilia (parasites, drugs, malignancies) and then addresses pulmonary “mimics”.Conclusions:An algorithm combining exclusion of secondary causes with organ and endotype profiling enables targeted therapy and reduced glucocorticoid exposure.

Background Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. Results We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. Conclusions These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma. Graphical Abstract

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients. We hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity. Herein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases. A review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17-87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection. Current treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.

The rate of caesarean section delivery (CSD) is increasing worldwide. It remains unclear whether disruption of mother-to-neonate transmission of microbiota through CSD occurs and whether it affects human physiology. Here we perform metagenomic analysis of earliest gut microbial community structures and functions. We identify differences in encoded functions between microbiomes of vaginally delivered (VD) and CSD neonates. Several functional pathways are over-represented in VD neonates, including lipopolysaccharide (LPS) biosynthesis. We link these enriched functions to individual-specific strains, which are transmitted from mothers to neonates in case of VD. The stimulation of primary human immune cells with LPS isolated from early stool samples of VD neonates results in higher levels of tumour necrosis factor (TNF-α) and interleukin 18 (IL-18). Accordingly, the observed levels of TNF-α and IL-18 in neonatal blood plasma are higher after VD. Taken together, our results support that CSD disrupts mother-to-neonate transmission of specific microbial strains, linked functional repertoires and immune-stimulatory potential during a critical window for neonatal immune system priming. The effects of caesarean section delivery on mother-to-neonate transmission of microbiota are unclear. Here the authors show that caesarean section delivery can affect the transmission of specific microbial strains and the immunomodulatory potential of the microbiota.

Interleukin‐5 (IL‐5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL‐5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL‐5 were analysed. The results showed that cardiac IL‐5 expression was time‐ and dose‐dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL‐5‐knockout (IL‐5−/−) mice were used to observe the effects of IL‐5 knockout on Ang II‐induced cardiac remodelling. We found knockout of IL‐5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross‐sectional areas and worsened cardiac dysfunction in Ang II‐infused mice. IL‐5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL‐5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31‐201. The effects of IL‐5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31‐201. Finally, the effects of IL‐5 on macrophage differentiation and macrophage‐related cardiac hypertrophy and fibrosis were analysed in vitro. IL‐5 knockout significantly increased the Ang II‐induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co‐cultured with macrophages, and this effect was reversed by S31‐201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co‐cultured. In conclusions, IL‐5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II‐infused mice. IL‐5 may be a potential target for the clinical prevention of cardiac remodelling.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and chronic airway inflammation, traditionally managed with inhaled bronchodilators and corticosteroids. However, a significant subset of patients exhibits suboptimal response to these inhaled therapies, and disease progression remains challenging to control effectively. Recent advances in understanding the inflammatory pathways underlying COPD have led to the development of biologic agents targeting critical cytokines and their receptors, including IL-4 receptor (IL-4R), IL-5, IL-5 receptor (IL-5R), IL-33, ST2, and thymic stromal lymphopoietin (TSLP). Emerging drugs such as JKN2401, TQC2731, and tezepelumab demonstrate promising therapeutic potential by modulating these specific inflammatory mediators. This review comprehensively summarizes the pathophysiological roles of these cytokines in COPD, the current progress in biologic drug development targeting these molecules, and the outcomes of recent clinical trials. By elucidating these novel therapeutic avenues, the article aims to provide a theoretical foundation and clinical guidance for precision medicine approaches in COPD management beyond conventional inhaled treatments.

Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = −0.454, P <0.001), TNF-α (g = −0.202, P = 0.015), IL-10 (g = −0.566, P = 0.012), and CCL-2 (g = −1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.

Background Benralizumab is a monoclonal antibody that binds to the human interleukin-5 (IL-5) receptor (IL-5R), thereby preventing IL-5 from binding to its receptor and inhibiting differentiation and maturation of eosinophils in the bone marrow. Because of its recent marketing approval, sufficient real-life evidence is lacking to confirm the efficacy and safety data from clinical trials. The purpose of this study was to evaluate the efficacy and safety of benralizumab for the treatment of severe refractory eosinophilic asthma in a real-world cohort of patients. Methods This was a cross-sectional multicentre study of consecutive patients with severe refractory eosinophilic asthma who received treatment with benralizumab during at least 6 months. Patient follow-up was performed in specialised severe asthma units. Results A total of 42 patients were enrolled and treated with benralizumab. Asthma control, as measured by the asthma control test (ACT), improved in all patients both at 3 months of treatment compared with baseline (13.9 ± 4 vs 20.1 ± 3.7, p  < 0.001) and at 6 months of treatment compared with the results obtained at 3 months (20.1 ± 3.7 vs 21 ± 2.7, p  = 0.037). Similarly, the number of emergency department visits decreased both at 3 months compared with baseline (1 [IR:0.7] vs 0 [IR:0.75], p  < 0.001) and at 6 months compared with the results at 3 months (0 [IR:0.75] vs 0 [IR:0], p  = 0.012). Reductions in the number of oral corticosteroid cycles, percentage of corticosteroid-dependent patients, and mean daily dose of oral or inhaled corticosteroid were also evidenced. Finally, mean lung function improvement was 291 mL ( p  < 0.001), and FEV1% improved both at 3 months compared with baseline (64.4 ± 9.3 vs 73.1 ± 9.1, p  < 0.001) and at 6 months compared to 3 months (73.1 ± 9.1 vs 76.1 ± 12, p  = 0.002). Side effects were mild and did not lead to treatment discontinuation. Conclusions This study confirms the efficacy and safety of benralizumab in a real-life setting with improved asthma control and lung function, and a reduced oral and inhaled corticosteroid use as well as fewer emergency department visits. In addition to a rapid initial improvement, it appears that patients continue to improve during the first 6 months of treatment.

As a part of the innate immune system, eosinophils are recruited during infectious diseases, to release their characteristic cytotoxic granules and catch pathogens in extracellular traps. Moreover, eosinophils have a crucial role in autoimmune diseases, for example allergies. The isolation of these densest and lowest abundant leukocytes is cost-and labor intense. This sets restrictions on many aspects of eosinophilic research. In this study, we performed a thorough characterization and functional assessment of the HL-60 clone 15 (HC15) cell line, which can be differentiated into eosinophil-like cells, to investigate its potential in eosinophil research. HC15 cells were differentiated with sodium butyrate with or without IL-5 and cells were characterized and compared to primary eosinophils, neutrophils and peripheral blood mononuclear cells. Cell features were analyzed using proteomics, morphologic assessment, RT-qPCR, immunofluorescent staining and flow cytometry. Based on these results, functional tests were performed, including transwell migration assays, flow cytometry-based aggregate formation assays, immunofluorescent microscopy-based adherence assays to endothelial cells and flow cytometry- and ELISA-based activation assays. The proteomes of the cell line cells differed from those of primary eosinophils and neutrophils. Differentiation of HC15 cells enhanced the expression of GATA-1 and altered the expression of surface markers IL-5R, EMR1, and TREM-1. Differentiated HC15 cells overexpressed the granule protein EPX compared to primary eosinophils and induced a distinct inflammatory milieu by secreting CCL-5, EPX and IL-8. The addition of IL-5 during differentiation increased this effect. Cell line cells responded weaker to activation than primary eosinophils but showed a similar migration and adherence pattern in multiple assays. These features were mostly unaffected by differentiation. Differentiation of HC15 cells induces an eosinophil lineage-committed precursor state. Hence, the differentiated cell line cells lacked characteristic features of eosinophils such as morphologic attributes, surface marker expression and the capacity to be activated. However, the cells were able to migrate, form aggregates with platelets and similarly adhere to endothelial cells as primary eosinophils. It is, therefore, advisable to use the cell line as an eosinophilic model only in research questions related to chemotaxis and migration.

Background Benralizumab, a monoclonal antibody targeting the human interleukin-5 (IL-5) receptor (IL-5R), was used before marketing authorisation in Spain in a real world setting as part of an early-access programme (EAP) to treat patients with severe eosinophilic asthma with prior insufficient response or intolerance to anti-IL5 treatment (mepolizumab or reslizumab). The objective of this study is to describe the patient profile candidate for treatment and to assess benralizumab effectiveness. Methods This is an observational, retrospective, multicentre study in severe eosinophilic asthma patients refractory to other biological agents targeting the IL-5 pathway. Baseline characteristics included closest data, from the previous 12 months, to benralizumab treatment onset (index date). Patients were followed until the last treatment dosage while EAP was active (March to December 2018). Effectiveness was evaluated versus baseline, in patients who received at least three doses, with asthma control test (ACT), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), annual severe exacerbation rate, oral corticosteroids treatment (OCS) and asthma-related healthcare resources utilization. Results Twenty-seven patients treated with benralizumab were included in the analysis. Effectiveness was assessed in 19 patients. Both questionnaires showed clinically meaningful differences, i.e. ACT score ≥ 3 and MiniAQLQ score ≥ 0.5, compared with baseline [mean (SD), 3.3 (6.8) and 1.2 (1.9), respectively]. Patients treated with OCS decreased during follow-up from 88.9% (n = 24/27) at baseline to 78.9% (n = 15/19) and 31.6% (n = 6/19) had an OCS dose reduction ≥ 50%. The difference in annual severe exacerbation rate during follow-up showed a significant reduction vs. baseline (2.12 per patient-year, 95% CI 0.99–3.24, p = 0.002). The differences in annual rate of non-scheduled primary care and specialist visits during follow-up indicated a significant decrease [2.28 per patient-year (95% CI 1.55–3.01; p < 0.001) and 1.47 per patient-year (95% CI 0.65–2.30; p = 0.004), respectively], as well as the difference in annual rate of number of emergency department visits [1.18 per patient-year (95% CI 0.51–1.85; p = 0.007)]. Conclusions These results suggest that severe eosinophilic asthma patients receiving benralizumab, presented clinically meaningful improvement in asthma control and asthma-related QoL as well as OCS dose reduction. Results also aim to significant reductions in annual severe exacerbation rates, non-scheduled primary care and specialist visits, and emergency department visits rates.