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Objective To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations. Conclusion This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.

BACKGROUND Type 2 inflammation is characterized by enhanced activity of interleukin (IL)-4, -5 and -13, and treatments targeting these pathways are available for treatment of severe asthma. At present, the pattern of pathway activity and the implications overlapping of pathway activity are unknown. OBJECTIVE We hypothesized that clustering of airway mRNA expression would identify distinct molecular subtypes of severe asthma and thereby uncover the prevalence and overlap of pathway activity. METHODS Sputum mRNA expression of genes related to expression of IL-5(CLC, CPA3 and DNASE1L3), IL-13(IL13Ra1, TNFSF14 and SERPINB2), T1/Th17 activity(IL1B, ALPL and CXCR2) and in vitro response to corticosteroids (FKBP512) and mepolizumab (ARAP3) was analysed in patients (n = 109) with severe asthma and healthy controls (n = 22). A cluster analysis of gene expression was performed. The response to a short course of OCS was assessed in a subset of patients (n = 29). RESULTS Five molecular clusters were identified. Three had abundant T2 gene expression of which two (n = 39 and n = 9) were characterized by abundant expression of both IL-13- and IL-5-related genes. The last (n = 6) had only abundant IL-5-related gene expression. These T2-high molecular clusters could not be distinguished using T2 biomarkers. T2- and Th1/Th17-related mRNA expression were co-expressed across all clusters. OCS significantly reduced T2 gene expression (CLC, IL13Ra1, SERPINB2 and ARAP3) and significantly increase expression of Th1/Th17-related genes (ALPL and CXCR2). CONCLUSIONS AND CLINICAL RELEVANCE Clustering of airway mRNA expression identified five molecular clusters of severe asthma of which three were considered T2 high. Co-expression of IL-5- and IL-13-related genes at moderate levels was present in almost half of patients, while marked elevated expression of both was rare. In contrast to IL-5, clusters with isolated IL-13- and Th1/Th17-related gene expression were not identified.

Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin-5 (IL-5). Treatment is challenging because L-HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L-HES. In all, 25 studies were selected; two were randomised controlled trials of IL-5 blockade, which included some patients with L-HES, and the rest were observational studies. Corticosteroids are often used as first-line therapy, but patients with L-HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon-alpha (IFN-α), anti-IL-5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T-cell activation and proliferation, or IL-5 directly. Although effective, IFN-α and cyclosporine were commonly reported to cause side-effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti-IL-5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L-HES.

Background Asthma and some chronic rhinosinusitis (CRS) subtypes are mediated by similar pathophysiologic mechanisms. The purpose of this study was to evaluate the effects of biologic therapy for asthma on co-existent CRS in the "real-world" setting. Methods A review of electronic health records (2016-2019) at Mayo Clinic was conducted to identify asthma patients treated with biologics who had co-existent CRS. Matched-pair analyses compared pretherapy and posttherapy Lund-Mackay computed tomography (CT) scores and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Performance of endoscopic sinus surgery (ESS) after initiating biologics was studied. Results We identified 247 patients who received anti-asthma biologic therapy and had co-existent CRS. Of these, 181 patients (73.3%) had CRS with nasal polyposis (CRSwNP) and 66 (26.7%) had CRS without nasal polyposis (CRSsNP). The biologics utilized were omalizumab (51.0%), mepolizumab (46.6%), benralizumab (10.5%), reslizumab (1.6%), and dupilumab (2.4%). Anti-interleukin-5 (anti-IL-5) intervention was associated with significant improvement in CT scores (CRS overall, CRSwNP subgroup, CRSsNP subgroup) and SNOT-22 scores (CRS overall, CRSwNP subgroup). Patients on omalizumab had a decrease in CT scores, but not SNOT-22 scores. ESS was performed in 206 patients (84.1%); 55 (22.3%) underwent surgery post-biologic intervention (anti-IL-5: 16.5%; omalizumab 27.8% of patients). Conclusion Anti-IL-5 agents were associated with improved CT and SNOT-22 scores in the overall CRS group and in CRSwNP subgroup; CRSsNP patients showed improved CT scores only. Omalizumab improved CT but not SNOT-22 scores. ESS was performed in 22% of patients after initiating biologics. These real-world results may influence future trial designs and clinical applications of biologics for CRS. ©2021 ARSAAOA, LLC.

Randomized control trials performed in selected populations of severe eosinophilic asthmatics have shown that mepolizumab, an anti-IL5 therapy, was able to reduce exacerbations and OCS maintenance dose and in some studies, to improve asthma control and lung function.The aim of this study was to confirm the results of the RCTs in real-life in a population of 116 severe eosinophilic asthmatics treated with mepolizumab and who were followed up at the asthma clinic every month for at least 18 months. Severe asthmatics underwent FENO, lung function, asthma control and quality of life questionnaires, sputum induction and gave a blood sample at baseline, after 6 months and then every year.We found a significant reduction in exacerbations by 85% after 6 months (P.0001), which was maintained over time. We also found a significant and maintained reduction by 50% in the dose of oral corticosteroids (P.001). Patients improved their ACT (+5.31pts, p0.0001) ACQ (-1.13pts, P.0001) and their AQLQ score (+1.24, P.0001) at 6 months and this was maintained during follow-up. Only 37% reached asthma control (ACQ1.5, ACT20). We observed a progressive increase in post-BD FEV1 that reached significance after 18 months (190ml or 11%, P.01). Patients improving their FEV1had higher baseline sputum eosinophils than those not improving airway caliber. We found a significant reduction in sputum eosinophil counts by 60% after 6 months (P.01) and a maintained reduction in blood eosinophil counts by 98% (P.0001).In our real-life study, we confirm the results published in the RCTs showing a sharp reduction in exacerbation and oral corticosteroids dose and an improvement in asthma control and quality of life.Mepolizumab is efficient in severe eosinophilic asthma in real life.

This study compared the pharmacokinetic (PK) profile of a new liquid formulation of mepolizumab with the established lyophilized formulation. In this open‐label, parallel‐group, single‐dose study (NCT03014674; GSK ID: 204958), healthy participants were randomized (1:1:1) to receive a single mepolizumab dose (100 mg) administered subcutaneously as liquid in a single‐use prefilled syringe or single‐use prefilled autoinjector, or as a lyophilized formulation. Maximum plasma concentration, area under the plasma concentration–time curve from time zero (predose) to time of last quantifiable concentration (AUC0–t), and AUC from time zero to infinity (AUC0–∞) as well as additional PK parameters, safety assessments, and blood eosinophil count were evaluated. In total, 244 participants received study drug. All PK parameters were similar across the 3 groups; 90% confidence intervals for maximum plasma concentration, AUC0–t, and AUC0–∞ treatment ratios (liquid prefilled syringe or autoinjector vs lyophilized formulation) were within conventional bioequivalence bounds (0.80‐1.25), demonstrating statistical PK comparability. On‐treatment adverse event incidence was 29% to 38%. Mepolizumab liquid formulation administered via prefilled syringe or autoinjector had similar PK properties to the lyophilized formulation, with no safety concerns identified.

Five biologicals have been approved for severe eosinophilic asthma, a well-recognized phenotype. Systematic reviews (SR) evaluated the efficacy and safety of benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab (alphabetical order) compared to standard of care for severe eosinophilic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma-related outcomes were evaluated for each of the biologicals. The risk of bias and the certainty of the evidence were assessed using GRADE. 19 RCTs (three RCTs for benralizumab, three RCTs for dupilumab, three RCTs for mepolizumab, five RCTs for omalizumab and five RCTs for reslizumab), including subjects 12 to 75 years old (except for omalizumab including also subjects 6-11 years old), ranging from 12 to 56 weeks were evaluated. All biologicals reduce exacerbation rates with high certainty of evidence: benralizumab incidence rate ratio (IRR) 0.53 (95% CI 0.39 to 0.72), dupilumab (IRR) 0.43 (95% CI 0.32 to 0.59), mepolizumab IRR 0.49 (95% CI 0.38 to 0.66), omalizumab (IRR) 0.56 (95% CI 0.40 to 0.77) and reslizumab (IRR) 0.46 (95% CI 0.37 to 0.58). Benralizumab, dupilumab and mepolizumab reduce the daily dose of oral corticosteroids (OCS) with high certainty of evidence. All evaluated biologicals probably improve asthma control, QoL and FEV1 , without reaching the minimal important difference (moderate certainty). Benralizumab, mepolizumab and reslizumab slightly increase drug-related adverse events (AE) and drug-related serious AE (low to very low certainty of evidence). The incremental cost-effectiveness ratio per quality-adjusted life year value is above the willingness to pay threshold for all biologicals (moderate certainty). Potential savings are driven by decrease in hospitalizations, emergency and primary care visits. There is high certainty that all approved biologicals reduce the rate of severe asthma exacerbations and for benralizumab, dupilumab and mepolizumab for reducing OCS. There is moderate certainty for improving asthma control, QoL, FEV1 . More data on long-term safety are needed together with more efficacy data in the paediatric population.

OBJECTIVE: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real-life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. METHODS: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015-2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ���4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. RESULTS: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty-five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty-two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). CONCLUSION: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial.

BACKGROUND Chronic rhinosinusitis (CRS) refractory to medical and surgical treatment is challenging. It impacts patients' quality of life significantly. The pathophysiology of CRS has some similarities to allergic asthma and allergic rhinitis (AR) and includes eosinophilia, T-helper cell 2 cytokines, and local immunoglobilin E formation. Monoclonal antibody therapy has been used successfully in asthma and AR and more recently in CRS. Our was aim to systematically review the literature and identify the role of monoclonal antibodies (MAbs) in the treatment of CRS with polyps (CRSwNP) and without polyps (CRSsNP), especially with regard to comparability with current medical treatment, efficacy, and risk of complications. In addition, the role of surgery and biologics was evaluated. METHODS We identified at total of 5341 relevant studies after a comprehensive database search. Six studies met the inclusion criteria, all 6 randomized, controlled trials. RESULTS Treatment with omalizumab and mepolizumab demonstrated improvements in endoscopic nasal polyp score (EPS) and symptoms score in patients with CRSwNP when compared with placebo. Reslizumab reduced nasal polyp size in patients with raised intranasal interleukin-5 levels. Dupilumab treatment resulted in a 70% reduction in EPS compared with 20% in the placebo group (p < 0.001). These MAbs target different inflammatory markers involved in the pathophysiology of CRSwNP. None of the studies reported on CRSsNP or combined surgery with biologics. No severe adverse events were reported. CONCLUSION Evidence demonstrates that use of MAbs leads to clinical improvement in CRSwNP. However, further research is required to determine their long-term effects, comparability to other medical treatments, and potential side effects.

Immune checkpoint inhibitors (ICIs) have been used for various carcinomas. However, immune‐related adverse events have been observed. There have been few reports of treatment with biologics for severe bronchial asthma induced by ICI; therefore, their efficacy is unknown. We report two cases of severe bronchial asthma requiring systemic steroid administration while using anti‐programmed death‐ligand 1 (PD‐L1) antibody for advanced non‐small‐cell lung cancer. The anti‐interleukin‐5 antibody, mepolizumab, was introduced, resulting in the discontinuation of systemic prednisolone and good asthma control. These reports suggest that treatment with biologics may be effective in severe cases of poorly controlled bronchial asthma during ICI therapy., We report two cases of severe bronchial asthma requiring systemic steroid administration while using anti‐programmed death‐ligand 1 (PD‐L1) antibody for advanced non‐small cell lung cancer. In each case, mepolizumab was introduced, resulting in discontinuation of systemic prednisolone and good control of asthma.

Asthmatic children usually reach good control of symptoms with a low-medium dose of inhaled corticosteroids (ICS), but approximately 5% has severe asthma. In this group of patients, when the diagnosis of severe asthma is confirmed, biologic agents have to be considered when there is no control of the symptoms despite conventional treatment with controllers according to guidelines. At present, the only biologic agent available in clinical practice for severe asthma treatment in children (6-18 years) is omalizumab. Mepolizumab has been recently approved by EMA for pediatric use. Reslizumab is a monoclonal antibody anti-IL-5 that has been approved for severe eosinophilic asthma treatment only in patients >12 years. Because of their action on specific molecular targets of the asthma pathophysiology, biologic agents are very promising therapeutic options for severe asthmatic patients based on individual endotypes.

Background Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. Methods Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). Results There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Conclusion Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different., In a chronic obstructive pulmonary disease (COPD) cohort (EvA, n = 283), 12 genes, whereas in asthma cohort (UBIOPRED, n = 85), 1197 genes in bronchial epithelial brushes were correlated with a blood eosinophil count. The gene CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Objectives There are no published reports for anti‐interleukin‐5 therapy in children

Background Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. Objective To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. Methods OSMO was a multicenter, open‐label, single‐arm, 32‐week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high‐dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)‐5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ‐5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ‐5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. Results At Week 32 (intent‐to‐treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ‐5 and SGRQ total scores were −1.45 (0.107) and −19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ‐5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. Conclusion After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported., Minimal clinically important difference for improvement in asthma control questionnaire‐5 and St. George's Respiratory Questionnaire total scores was achieved by 77% and 79% of patients, respectively. Annualized rate of clinically significant exacerbations was reduced from 3.26 to 1.18 events/year. Safety and immunogenicity profiles of mepolizumab were consistent with previous placebo‐controlled trials in severe eosinophilic asthma.

Background Activated eosinophils cause major pathology in stable and exacerbating asthma; however, they can also display protective properties like an extracellular antiviral activity. Initial murine studies led us to further explore a potential intracellular antiviral activity by eosinophils. Methods To follow eosinophil‐virus interaction, respiratory syncytial virus (RSV) and influenza virus were labeled with a fluorescent lipophilic dye (DiD). Interactions with eosinophils were visualized by confocal microscopy, electron microscopy, and flow cytometry. Eosinophil activation was assessed by both flow cytometry and ELISA. In a separate study, eosinophils were depleted in asthma patients using anti‐IL‐5 (mepolizumab), followed by a challenge with rhinovirus‐16 (RV16). Results DiD‐RSV and DiD‐influenza rapidly adhered to human eosinophils and were internalized and inactivated (95% in ≤ 2 hours) as reflected by a reduced replication in epithelial cells. The capacity of eosinophils to capture virus was reduced up to 75% with increasing severity of asthma. Eosinophils were activated by virus in vitro and in vivo. In vivo this correlated with virus‐induced loss of asthma control. Conclusions This previously unrecognized and in asthma attenuated antiviral property provides a new perspective to eosinophils in asthma. This is indicative of an imbalance between protective and cytotoxic properties by eosinophils that may underlie asthma exacerbations., 1,19 – dioctadecyl ‐ 3, 3, 39, 39 – tetramethylindocarbocyanine (DiD)‐respiratory syncytial virus and DiD‐influenza adhered to human eosinophils. Both viruses were internalized and inactivated by eosinophils. The capacity of eosinophils to capture virus was reduced with increasing severity of asthma. IL‐5 Tg: IL‐5 transgenic; RSV: Respiratory syncytial virus; WT: Wild‐type

Severe asthma is a relatively uncommon condition in children but one which causes morbidity, occasionally mortality, and is a challenging condition to manage. There are several definitions of severe asthma, which have a common theme of poor control despite high dose inhaled corticosteroid treatment. Depending on the definition chosen, the prevalence of severe childhood asthma may be up to 5% within populations with asthma. Collectively, there is some evidence that the treatments used in severe asthma are beneficial, but a solid evidence-base is lacking for many treatments and some treatments have recognized side effects. Evidence supporting the use of maintenance oral prednisolone and intramuscular triamcinolone is weak. Response to systemic corticosteroids is heterogeneous and recognizing phenotypes or endotypes may identify those most likely to gain maximal benefit from treatment. For children aged 6 to 11 years, the anti-IgE biologic omalizumab is effective and anti-IL-5 agent (mepolizumab) has recently been licenced in Europe (but not the US). Biologics, which are licenced for >11 year olds include omalizumab, mepolizumab, benralizumab, reslizumab, and dupilumab. There is plenty that the clinician can offer to the child and adolescent with severe asthma in 2019, including nontherapeutic and therapeutic interventions. To manage severe asthma, practitioners from broad specialities must establish and maintain a close therapeutic relationship with patients. Looking beyond 2019, more treatment options will emerge for severe childhood asthma, and clinical teams will need to continue weighing up benefits and harms.

Monoclonal antibody therapies are effective for many but not all people with severe asthma. Precision medicine guides treatment selection using biomarkers to select patients most likely to respond according to their inflammatory endotypes. However, when assessing response to treatment, greater precision is required. We report a case series describing treatment response to mepolizumab in four severe asthma patients, assessed by traditional methods and with objective ventilation/perfusion single photon emission computed tomography (V‐P SPECT). In this series, patients with severe asthma received mepolizumab treatment with clinical outcomes recorded at commencement and at approximately 16 weeks post‐treatment initiation. V‐P SPECT imaging was performed before and after treatment to determine ventilation heterogeneity and perfusion, and its ability to assess treatment responsiveness. V‐P SPECT shows promise as an objective measure to assess lung ventilation and perfusion to observe and assess responsiveness to mepolizumab. With quantification, this measure may allow better precision in determining treatment improvements., We report a case series describing treatment response to mepolizumab in four severe asthma patients, assessed by traditional methods and with objective ventilation/perfusion single photon emission computed tomography (V‐P SPECT). In this series, patients with severe asthma received mepolizumab treatment with clinical outcomes recorded and V‐P SPECT imaging performed at commencement and at approximately 16 weeks post‐treatment initiation. V‐P SPECT shows promise as an objective measure to assess lung ventilation and responsiveness to mepolizumab, allowing better precision in determining treatment improvements.

See related Letter.

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, and reslizumab-1) included 1236 adults, with follow-up of 20-64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20-0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT-22 (MD -19.14; 95% CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95% CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78-0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10-1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD -15.65; 95% CI -16.16 to -15.13), with increased TAE (RR 1.73; 95% CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64-0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95% CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41-6.50). The evidence for reslizumab is very uncertain.

BACKGROUND: We aimed to evaluate the effectiveness of different antibody therapies on nasal polyp symptoms in patients treated for severe asthma. METHODS: We performed a retrospective analysis of patients with severe asthmaand comorbid CRSwNP who were treated with anti-IgE, anti-IL-5/R or anti-IL-4R. CRSwNP symptom burden was evaluated before and after 6months of therapy. RESULTS: Fifty patients were included hereof treated with anti-IgE: 9, anti-IL-5/R: 26 and anti-IL-4R: 15 patients. At baseline median SNOT-20 was similar among groups (anti-IgE: 55, anti-IL-5/R: 52 and anti-IL-4R: 56, p=0.76), median visual analogue scale (VAS) for nasal symptoms was 4, 7 and 8 (p=0.14) and VAS for total symptoms was higher in the anti-IL-4R group (4, 5 and 8, p=0.002). After 6months SNOT-20 improved significantly in all patient groups with median improvement of anti-IgE: -8 (p&nbsp

Background Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospital admissions, disease-related morbidity and mortality. COPD is a heterogeneous disease with distinct inflammatory phenotypes, including eosinophilia, which may drive acute exacerbations in a subgroup of patients. Monoclonal antibodies targeting interleukin 5 (IL-5) or its receptor (IL-5R) have a role in the care of people with severe eosinophilic asthma, and may similarly provide therapeutic benefit for people with COPD of eosinophilic phenotype. Objectives To assess the efficacy and safety of monoclonal antibody therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) compared with placebo in the treatment of adults with COPD. Search methods We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, clinical trials registries, manufacturers' websites, and reference lists of included studies. Our most recent search was 23 September 2020. Selection criteria We included randomised controlled trials comparing anti-IL-5 therapy with placebo in adults with COPD. Data collection and analysis Two review authors independently extracted data and analysed outcomes using a random-effects model.The primary outcomes were exacerbations requiring antibiotics or oral steroids, hospitalisations due to exacerbation of COPD, serious adverse events, and quality of life. We used standard methods expected by Cochrane. We used the GRADE approach to assess the certainty of the evidence. Main results Six studies involving a total of 5542 participants met our inclusion criteria. Three studies used mepolizumab (1530 participants), and three used benralizumab (4012 participants). The studies were on people with COPD, which was similarly defined with a documented history of COPD for at least one year. We deemed the risk of bias to be generally low, with all studies contributing data of robust methodology. Mepolizumab 100 mg reduces the rate of moderate or severe exacerbations by 19% in those with an eosinophil count of at least 150/μL (rate ratio (RR) 0.81, 95% confidence interval (CI) 0.71 to 0.93; participants = 911; studies = 2, high-certainty evidence). When participants with lower eosinophils are included, mepolizumab 100 mg probably reduces the exacerbation rate by 8% (RR 0.92, 95% CI 0.82 to 1.03; participants = 1285; studies = 2, moderate-certainty evidence). Mepolizumab 300 mg probably reduces the rate of exacerbations by 14% in participants all of whom had raised eosinophils (RR 0.86, 95% CI 0.70 to 1.06; participants = 451; studies = 1, moderate-certainty evidence); the evidence was uncertain for a single small study of mepolizumab 750 mg. In participants with high eosinophils, mepolizumab probably reduces the rate of hospitalisation by 10% (100 mg, RR 0.90, 95% CI 0.65 to 1.24; participants = 911; studies = 2, moderate-certainty evidence) and 17% (300 mg, RR 0.83, 95% CI 0.51 to 1.35; participants = 451; studies = 1, moderate-certainty evidence). Mepolizumab 100 mg increases the time to first moderate or severe exacerbation compared to the placebo group, in people with the eosinophilic phenotype (hazard ratio (HR) 0.78, 95% CI 0.66 to 0.92; participants = 981; studies 2, high-certainty evidence). When participants with lower eosinophils were included this difference was smaller and less certain (HR 0.87, 95% CI 0.75 to 1.0; participants = 1285; studies 2, moderate-certainty evidence). Mepolizumab 300 mg probably increases the time to first moderate or severe exacerbation in participants who all had eosinophilic phenotype (HR 0.77, 95% CI 0.60 to 0.99; participants = 451; studies = 1, moderate-certainty evidence). Benralizumab 100 mg reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.63, 95% CI 0.49 to 0.81; participants = 1512; studies = 2, high-certainty evidence). Benralizumab 10 mg probably reduces the rate of severe exacerbations requiring hospitalisation in those with an eosinophil count of at least 220/μL (RR 0.68, 95% CI 0.49 to 0.94; participants = 765; studies = 1, moderate-certainty evidence). There was probably little or no difference between the intervention and placebo for quality of life measures. Where there were differences the mean difference fell below the pre-specified minimum clinically significant difference. Treatment with mepolizumab and benralizumab appeared to be safe. All pooled analyses showed that there was probably little or no difference in serious adverse events, adverse events, or side effects between the use of a monoclonal antibody therapy compared to placebo. Authors' conclusions We found that mepolizumab and benralizumab probably reduce the rate of moderate and severe exacerbations in the highly selected group of people who have both COPD and higher levels of blood eosinophils. This highlights the importance of disease phenotyping in COPD, and may play a role in the personalised treatment strategy in disease management. Further research is needed to elucidate the role of monoclonal antibodies in the management of COPD in clinical practice. In particular, it is not clear whether there is a threshold blood eosinophil level above which these drugs may be effective. Studies including cost effectiveness analysis may be beneficial given the high cost of these therapies, to support use if appropriate.

Biologic agents, monoclonal antibodies that target highly-specific molecular pathways of inflammation, are becoming integrated into care pathways for multiple disorders that are relevant in otolaryngology and allergy. These conditions share common inflammatory mechanisms of so-called Type 2 inflammation with dysregulation of immunoglobulin E production and eosinophil and mast cell degranulation leading to tissue damage. Biologic agents are now available for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, eosinophilic granulomatosis with polyangiitis (EGPA), atopic dermatitis (AD), and chronic spontaneous urticaria (CSU). This paper summarizes the diagnosis and management of these conditions and critically reviews the clinical trial data that has led to regulatory approval of biologic agents for these conditions.

We report a patient with idiopathic hypereosinophilic syndrome (I‐HES) who achieved remission with benralizumab after relapsing on mepolizumab. An 83‐year‐old man was admitted to Showa General Hospital after presenting with hypoxaemia and multiple erythematous lesions. He showed a marked increase in blood eosinophil count. Skin biopsy revealed an invasion of eosinophils in the dermis. He was diagnosed with I‐HES. He was commenced on prednisolone 40 mg/day with a plan to wean this over time after pulse steroid therapy for three days. Mepolizumab was added when the prednisolone dose was 25 mg/day. Unfortunately, at a prednisolone dose of 5 mg/day, there was evidence of disease progression and the patient was switched to benralizumab. Prednisolone was tapered again and, finally, the patient was in remission. Benralizumab targets interleukin (IL)‐5R and induces antibody‐dependent cell‐mediated cytotoxicity, thereby reducing the eosinophil counts in the tissue. This can be attributed to the therapeutic efficacy against I‐HES. We believe this report may help develop novel therapeutic strategies for I‐HES., We report a patient with idiopathic hypereosinophilic syndrome (I‐HES) who achieved remission with benralizumab after relapsing on mepolizumab. We believe this report may help develop novel therapeutic strategies for I‐HES.

Asthma is a common disease in childhood with a minority of affected children having severe therapy-resistant asthma (STRA). Children with STRA can be differentiated from those with mild-moderate disease by greater allergic sensitization, increased eosinophilic airway inflammation, increased airway remodelling and reduced corticosteroid responsiveness. The aetiology of STRA in children is multifactorial but allergy seems to play a key role. Many children with asthma have coexisting allergic disease, and severe rhinitis seems to be an important driver of STRA in children. Allergies to foods, moulds, pollen and pets have also been associated with severe asthma exacerbations. Identifying allergens that are driving asthma symptoms in children with STRA may provide additional strategies for improving their disease control. Avoidance strategies may be possible. Additional monoclonal antibody therapy with Omalizumab or Mepolizumab may be helpful in children with clinically important polysensitization.

IL‐5 is an important cytokine for priming and survival of mature eosinophils and for proliferation and maturation of their progenitors. Hence, IL‐5(Rα) targeting will be increasingly used in diseases where eosinophils are the key immune effector cells such as eosinophilic asthma (EA), hypereosinophilic syndrome (HES), eosinophilic esophagitis (EE), and eosinophilic granulomatosis with polyangiitis (EGPA). Therefore, several neutralizing monoclonal antibodies directed against IL‐5 (mepolizumab and reslizumab) and its receptor IL‐5Rα (benralizumab) have found or will find their way to the clinic. While the clinical effect of these drugs has been extensively investigated and reviewed, the understanding of the underlying immunological and hematological mechanisms remains less clear. This review will discuss the translational outcomes of treatment with these monoclonal antibodies in humans to shed light on the mechanisms underlying the main immunological and hematological findings from these clinical trials in humans.

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Background Disseminated herpes zoster infection occurs mostly in immunocompromised hosts. There have been recent reports of disseminated zoster with chemotherapeutic regimens and newer monoclonal antibodies. Case report The present case describes a 61-year-old patient presenting with disseminated herpes zoster after initiation of benralizumab, an anti-IL-5 monoclonal antibody for severe persistent asthma. His initial vesicular lesions limited to left lumbar dermatomes progressed extensively resulting in dissemination on his body. The diagnosis was confirmed with PCR and he had remarkable clinical improvement with acyclovir and supportive medical management. Conclusion Clinical trials have reported an association of mepolizumab, another anti-IL-5 monoclonal antibody with herpes zoster. This report of herpes zoster following initiation of benralizumab might suggest a possibility of a class effect of anti-IL-5 monoclonal antibody.

Disease overview The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Diagnosis Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Risk stratification Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes which includes the major category “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2,” and the “MPN subtype, chronic eosinophilic leukemia, not otherwise specified” (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. Risk-adapted therapy The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g.