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.

Repeated sensitization of mice with microfilariae of Litomosoides sigmodontis induces pulmonary eosinophilia in an IL-33-dependent manner.

BACKGROUND: Eosinophilia is a hallmark of helminth infections and eosinophils are essential in the protective immune responses against helminths. Nevertheless, the distinct role of eosinophils during parasitic filarial infection, allergy and autoimmune disease-driven pathology is still not sufficiently understood. In this study, we established a mouse model for microfilariae-induced eosinophilic lung disease (ELD), a manifestation caused by eosinophil hyper-responsiveness within the lung. METHODS: Wild-type (WT) BALB/c mice were sensitized with dead microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis three times at weekly intervals and subsequently challenged with viable MF to induce ELD. The resulting immune response was compared to non-sensitized WT mice as well as sensitized eosinophil-deficient dblGATA mice using flow cytometry, lung histology and ELISA. Additionally, the impact of IL-33 signaling on ELD development was investigated using the IL-33 antagonist HpARI2. RESULTS: ELD-induced WT mice displayed an increased type 2 immune response in the lung with increased frequencies of eosinophils, alternatively activated macrophages and group 2 innate lymphoid cells, as well as higher peripheral blood IgE, IL-5 and IL-33 levels in comparison to mice challenged only with viable MF or PBS. ELD mice had an increased MF retention in lung tissue, which was in line with an enhanced MF clearance from peripheral blood. Using eosinophil-deficient dblGATA mice, we demonstrate that eosinophils are essentially involved in driving the type 2 immune response and retention of MF in the lung of ELD mice. Furthermore, we demonstrate that IL-33 drives eosinophil activation in vitro and inhibition of IL-33 signaling during ELD induction reduces pulmonary type 2 immune responses, eosinophil activation and alleviates lung lacunarity. In conclusion, we demonstrate that IL-33 signaling is essentially involved in MF-induced ELD development. SUMMARY: Our study demonstrates that repeated sensitization of BALB/c mice with L. sigmodontis MF induces pulmonary eosinophilia in an IL-33-dependent manner. The newly established model recapitulates the characteristic features known to occur during eosinophilic lung diseases (ELD) such as human tropical pulmonary eosinophilia (TPE), which includes the retention of microfilariae in the lung tissue and induction of pulmonary eosinophilia and type 2 immune responses. Our study provides compelling evidence that IL-33 drives eosinophil activation during ELD and that blocking IL-33 signaling using HpARI2 reduces eosinophil activation, eosinophil accumulation in the lung tissue, suppresses type 2 immune responses and mitigates the development of structural damage to the lung. Consequently, IL-33 is a potential therapeutic target to reduce eosinophil-mediated pulmonary pathology.

Daptomycin-induced eosinophilic pneumonia.

ABSTRACT: Daptomycin-induced eosinophilic pneumonia (DIEP) is a rare complication of daptomycin use. Manifestations most commonly include fever, hypoxia, dyspnea, cough, eosinophilia, and lung changes on radiographs and CT. Patients typically have had recent daptomycin exposure and develop fever, dyspnea, infiltrates on chest radiograph, more than 25% eosinophils on bronchoalveolar lavage, and improvement of symptoms after withdrawal of daptomycin. Treatment includes discontinuation of daptomycin, corticosteroids, and supportive measures such as supplemental oxygen. Clinicians should have a high index of suspicion for DIEP in patients who develop new onset of pulmonary and systemic signs and symptoms after initiation of daptomycin.

Critical deterioration of chronic eosinophilic pneumonia during pregnancy.

Chronic eosinophilic pneumonia (CEP) is a rare, idiopathic interstitial lung disease characterised by the accumulation of eosinophils in the pulmonary interstitia and alveoli. Patients with CEP respond well to systemic corticosteroid therapy and infrequently progress to end-stage lung disease. We report a case of a woman in her 40s with previously stable, steroid-responsive CEP who experienced a critical deterioration of her CEP at 25 weeks of gestation during her third pregnancy. The patient was admitted to the intensive care unit due to respiratory failure requiring intubation and mechanical ventilation. Follow-up investigation revealed advanced fibrotic lung disease requiring long-term oxygen therapy and referral for double lung transplantation. While CEP infrequently advances to permanent parenchymal damage, this case demonstrates the potential for severe exacerbations in the setting of pregnancy and highlights pregnancy as a potential risk factor for disease progression, reinforcing the need for further research to define optimal monitoring and treatment strategies.

Features of severe asthma response to anti-IL5/IL5r therapies: identikit of clinical remission.

Introduction: Clinical remission (CliR) achievement has been recognized as a new potential outcome in severe asthma. Nevertheless, we still lack a detailed profile of what features could better identify patients undergoing clinical remission. In this study, we aim to address this issue, tracing a possible identikit of patients fulfilling remission criteria. Methods: We enrolled 266 patients with severe eosinophilic asthma (SEA) treated with a 12-month course of anti-IL5/IL5 receptor (IL5r) monoclonal antibodies. Patients with no exacerbation, OCS withdrawal, ACT ≥ 20 and FEV1 ≥ 80% after 1 year of biologic treatment were classified as in clinical remission. Results: 30.5% of the enrolled patients achieved remission after biologic administration. CliR group showed a lower number of baseline asthma exacerbations and better lung function parameters, with a trend for higher ACT scores and a less frequent history of a positive skin prick test. CliR achievement was unlikely in presence of a higher BMI, a positive skin prick test, an increased number of asthma exacerbations before biologic treatment, anti-muscarinic administration, and a previous diagnosis of EGPA, bronchiectasis or osteoporosis. In contrast, a better lung function, an increased blood eosinophilic count, the presence of chronic rhinosinusitis with nasal polyps and a more frequent use of reliever therapy predicts remission development. Changes in exacerbations number, OCS use, ACT scores and FEV1% between remittent and non-remittent patients arise at specific follow up timepoints and are positively associated with CliR achievement. Discussion: anti-IL5/IL5r biologics can induce CliR in a proportion of patients with SEA. Patients achieving remission demonstrate specific clinical, functional and inflammatory features, as well as a specific moment of improvement in all the CliR items.

Case Report: Allergic Bronchopulmonary Aspergillosis and Tropical Pulmonary Eosinophilia Co-Occurrence Masquerading as Refractory Allergic Bronchopulmonary Aspergillosis.

Pulmonary infiltrates with eosinophilia are a heterogeneous group of disorders that are characterized by pulmonary infiltrates on chest radiograph and elevated levels of eosinophils in the peripheral blood. Among patients with these disorders, reports of either allergic bronchopulmonary aspergillosis (ABPA) or tropical pulmonary eosinophilia (TPE) are common. However, the simultaneous occurrence of ABPA and TPE is not often reported. We present the case of a young man with a history of asthma who was diagnosed with ABPA and TPE. Initially, the patient exhibited a partial response to treatment of ABPA, but persistent symptoms and eosinophilia led to suspicion and subsequent diagnosis of TPE. With implementation of antifilarials and steroids, the patient experienced satisfactory clinical and serological improvements. This case underscores the importance of considering multiple diagnoses in patients with overlapping symptoms and highlights the need for comprehensive management strategies in complex lung diseases.

Monoclonal antibodies in idiopathic chronic eosinophilic pneumonia: a scoping review.

BACKGROUND: Idiopathic chronic eosinophilic pneumonia (ICEP) is a rare disease characterized by pulmonary radiological alterations, peripheral eosinophilia, and demonstrated pulmonary eosinophilia. Oral steroids (OSs) are the standard management, but relapses occur in up to 50% of patients during the decrease or suspension of steroids, usually requiring reinitiation of treatment, exposing patients to secondary events derived from the management. Management with monoclonal antibodies has been proposed in these cases to control the disease and limit the secondary effects. The objective is to describe the extent and type of evidence regarding the use of monoclonal antibodies for ICEP. METHODS: A panoramic review of the literature was performed. Observational and experimental studies of pediatric and adult populations that managed recurrent ICEP with monoclonal antibodies were included. Data search, selection, and extraction were performed by two independent reviewers. RESULTS: 937 studies were found. After applying the inclusion and exclusion criteria, 37 titles remained for the final analysis: a retrospective, observational, real-life study, two case series publications, and 34 case reports published in academic poster sessions and letters to the editor. In general, the use of monoclonal antibodies approved for severe asthma could be useful for the control of ICEP, since most of the results show a good response for clinical and radiological outcomes. Biological drugs seem to be a safer option for controlling relapses in ICEP, allowing lowering/suspension of OSs, and sometimes replacing them in patients intolerant to them, patients with significant comorbidities, and patients who have already developed adverse events. CONCLUSION: The extent of the evidence supporting management of ICEP with monoclonal antibodies against IL-5 and IgE (omalizumab) is limited, but it could be promising in patients who present frequent relapses, in cortico-dependent individuals, or in patients in whom the use of steroids is contraindicated. The extent of the evidence for management with dupilumab is more limited. Studies with better design and structure are needed to evaluate quality of life and outcomes during a clear follow-up period. To our knowledge, this is the first scoping review of the literature showing the extent of the evidence for the management of ICEP with monoclonal antibodies.

Identification and characterization of a novel nematode pan allergen (NPA) from Wuchereria bancrofti and their potential role in human filarial tropical pulmonary eosinophilia (TPE).

BACKGROUND: Tropical pulmonary eosinophilia (TPE) is a chronic respiratory syndrome associated with Lymphatic Filariasis (LF), a tropical parasitic infection of the human, transmitted by mosquitoes. The larval form of LF (microfilariae) are trapped in the lungs of TPE subjects have a major role in initiating the TPE syndrome. To date, there are no reports on the potential allergen that is responsible for generating parasite-specific IgE in TPE. METHODOLOGY/PRINCIPAL FINDINGS: In this project, we screened a cDNA expression library of the microfilarial stages of Wuchereria bancrofti with monoclonal IgE antibodies prepared from subjects with clinical filarial infections. Our studies identified a novel molecule that showed significant sequence similarity to an allergen. A blast analysis showed the presence of similar proteins in a number of nematodes parasites. Thus, we named this molecule as Nematode Pan Allergen (NPA). Subsequent functional analysis showed that NPA is a potent allergen that can cause release of histamine from mast cells, induce secretion of proinflammatory cytokines from alveolar macrophages and promote accumulation of eosinophils in the tissue, all of which occur in TPE lungs. CONCLUSIONS/SIGNIFICANCE: Based on our results, we conclude that the NPA protein secreted by the microfilariae of W. bancrofti may play a significant role in the pathology of TPE syndrome in LF infected individuals. Further studies on this molecule can help design an approach to neutralize the NPA in an attempt to reduce the pathology associated with TPE in LF infected subjects.

Moderate-High Blood Eosinophilia Is Associated with Increased Hospitalization and Other Asthma Comorbidities.

(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/µL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/µL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.

Characteristics and outcomes of patients enrolled in the Connect 360 benralizumab patient support programme in the UK: a retrospective cohort study.

BACKGROUND: Patient support programmes (PSPs) allow patients with chronic diseases to receive treatment and support at home. This study describes the Connect 360 PSP delivery and impact on patient-reported outcomes, satisfaction and adherence/persistence among benralizumab-treated patients with severe eosinophilic asthma (SEA). METHODS: A non-interventional retrospective cohort study using data collected during routine care in the Connect 360 PSP. All consenting enrollees (≥18 years) were included in the study. RESULTS: 746 patients formed the study cohort. Mean (SD) age was 53.7 (14.5) years on PSP entry; 38.3% were female (38.7% unknown). 79.6% of patients were experienced biological therapy users. Oral corticosteroid (OCS) use was reported in 48.4% of patients at baseline and 34.8% at 48 weeks. 8.2% of patients reported asthma hospitalisation in the previous 6 months at 24 weeks vs 3.0% at 48 weeks. Mean (SD) 6-item Asthma Control Questionnaire (ACQ-6) scores were 2.7 (1.5) at baseline vs 1.6 (1.3) at 48 weeks. Mean (SD) patient satisfaction scores remained high (4.5 of 5 (1.0) at baseline; 4.7 of 5 (0.6) at 48 weeks). 28.3% of patients were considered adherent at 24 weeks, increasing to 98.3% when supplemented with sales/delivery data (sensitivity analysis). Discontinuation from PSP/benralizumab was low at 24 (3.4%/3.0%) and 48 (12.6%/5.8%) weeks. CONCLUSIONS: Connect 360 PSP achieved high levels of satisfaction and persistence, with indications of positive outcomes including OCS use, hospitalisation and ACQ-6. The study was conducted during COVID-19, so it provides reassurance that patients with SEA receiving benralizumab may be supported safely and effectively at home.

Predictors of Early and Late Lung Function Improvement in Severe Eosinophilic Asthma on Type2-Biologics in the PRISM Study.

BACKGROUND: The determinants linked to the short- and long-term improvement in lung function in patients with severe eosinophilic asthma (SEA) on biological treatment (BioT) remain elusive. OBJECTIVE: We sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT. METHODS: 140 adult patients with SEA who received mepolizumab, dupilumab, or reslizumab were followed up for 6 months to evaluate improvement in forced expiratory volume in one second (FEV1). Logistic regression was used to determine the association between potential prognostic factors and improved lung function at 1 and 6 months of treatment. RESULTS: More than a third of patients with SEA using BioT showed early and sustained improvements in FEV1 after 1 month. A significant association was found between low baseline FEV1 and high blood eosinophil count and sustained FEV1 improvement after 1 month (0.54 [0.37-0.79] and 1.88 [1.28-2.97] odds ratios and 95% confidence interval, respectively). Meanwhile, among patients who did not experience FEV1 improvement after 1 month, 39% exhibited improvement at 6 months follow-up. A high ACT score measured at this visit was the most reliable predictor of late response after 6 months of treatment (OR and 95% CI 1.75 [1.09-2.98]). CONCLUSION: Factors predicting the efficacy of biological agents that improve lung function in SEA vary according to the stage of response.

Cryptogenic organizing pneumonia after withdrawal of systemic corticosteroids for chronic eosinophilic pneumonia and severe asthma under benralizumab treatment.

A 79-year-old woman with severe asthma developed chronic eosinophilic pneumonia (CEP). After CEP resolved with oral prednisolone at 30 mg/day, prednisolone was tapered and discontinued under introduction of benralizumab for her severe asthma. However, 8 weeks later, symptoms and bilateral patchy infiltrates on chest radiography appeared. Lymphocytosis without eosinophilia was seen in bronchoalveolar lavage fluids, and transbronchial biopsy indicated organizing pneumonia. Cryptogenic organizing pneumonia (COP) was diagnosed and resolved with prednisolone at 30 mg/day. Prednisolone was tapered to 3 mg/day without relapse of CEP or COP. This case suggests the overlap and similar pathogenesis of CEP and COP.

Acrylamide, an air pollutant, enhances allergen-induced eosinophilic lung inflammation via group 2 innate lymphoid cells.

Air pollution significantly impacts the aggravation of asthma. Exposure to acrylamide, a volatile organic compound in tobacco smoke, is associated with elevated risks of allergy-related outcomes among active smokers. As group 2 innate lymphoid cells (ILC2s) can act as an environmental sensor and significantly contribute to protease allergen-induced lung inflammation, we aimed to elucidate the causal relationship and how inhaled acrylamide worsens allergic lung inflammation via ILC2s. Intranasal acrylamide exposure at nanomolar levels significantly enhanced allergen-induced or recombinant mouse interleukin-33-induced lung inflammation in C57BL/6 mice or Rag1-/- mice, respectively. The cardinal features of lung inflammation included accumulated infiltration of ILC2s and eosinophils. Transcriptomic analysis revealed a gene expression pattern associated with proliferation-related pathways in acrylamide-treated ILC2s. Western blotting revealed significantly higher expression of Ras and phospho-Erk in acrylamide-treated ILC2s than the control, suggesting Ras-Erk signaling pathway involvement. Ex vivo and in vitro analysis showed that acrylamide treatment mainly increased Ki-67+ ILC2s and the cell number of ILC2s whereas PD98059, a highly selective Erk inhibitor, effectively counteracted the acrylamide effect. Intratracheal administration of acrylamide-treated ILC2s significantly enhanced eosinophil infiltration in Rag1-/- mice. This study suggests that airborne acrylamide may enhance the severity of allergen-induced airway eosinophilic inflammation, partly via altering ILC2 proliferative activity.

Factors Affecting the Ability to Discontinue Oral Corticosteroid Use in Patients with EGPA Treated with Anti-Interleukin-5 Therapy.

INTRODUCTION: Patients with eosinophilic granulomatosis with polyangiitis (EGPA) and some with severe eosinophilic asthma require continuous long-term oral corticosteroid (OCS) treatment for disease control. The anti-interleukin-5 agent, mepolizumab, has recently become available for the treatment of severe eosinophilic asthma and EGPA, with promising results and safety profiles. The proportion of patients with EGPA who discontinued oral steroids was 18% in the MIRRA trial. To compare patients with EGPA who were able to discontinue steroids with mepolizumab with those who could not. METHODS: Twenty patients with EGPA treated with mepolizumab were evaluated at Osaka Habikino Medical Center. The OCS dose, asthma control test score, fractional exhaled nitric oxide levels, peripheral eosinophil count, and spirometric parameters were evaluated before and after treatment. RESULTS: There was a significant reduction in the mean OCS dose from a prednisolone equivalent of 8.88 ± 4.99 mg/day to 3.18 ± 3.47 mg/day (p < 0.001). In this study, 40% of patients discontinued oral steroids. The most common reason for the failure to discontinue steroids in patients was poor asthma control. The percentage of predicted forced expiratory volume in 1 s significantly improved in patients with EGPA who could discontinue steroids after receiving mepolizumab. CONCLUSION: In this real-world study, treatment with mepolizumab for EGPA was associated with a significant reduction in OCS use; however, poor asthma control was identified as an inhibiting factor for steroid reduction.

Effectiveness of Mepolizumab in Patients with Severe Eosinophilic Asthma with/without Nasal Polyposis: A Real-Life Study.

INTRODUCTION: Asthma is one of the most common chronic diseases and affects around 334 million people worldwide. The estimated prevalence of severe asthma is 3-10% of the asthmatic population. Mepolizumab has demonstrated efficacy in reducing exacerbations, oral corticosteroid use, and improving quality of life, asthma control, and lung function in patients with severe eosinophilic asthma (SEA). Our study aimed to check the response to mepolizumab in a series of severe asthma patients regarding exacerbations, oral corticosteroid use, asthma control, quality of life, and lung function and to compare the response between patients with and without nasal polyps. METHOD: This is a retrospective, multicenter study of RE-ASGRAMUR (Register of Severe Asthma of the Region of Murcia) performed in eight hospitals of the Region of Murcia (Spain) under routine clinical practice conditions. We included patients diagnosed with SEA who completed at least 1 year of treatment with mepolizumab. We analyzed clinical characteristics, drug tolerance, and effectiveness: exacerbations, ACT, miniAQLQ, forced expiratory volume in 1 s (FEV1), and use of oral corticosteroids. We also compared the results between patients with and without nasal polyps. RESULTS: The median of exacerbations before treatment was 3 and decreased to 0 after treatment (mean decrease of 77.4%). The median diary oral prednisone intake was 15 mg before treatment and 5 mg after treatment (mean 56% reduction). We have obtained a significant improvement in other variables: ED visits and hospitalizations, asthma control (ACT), quality of life (miniAQLQ), and lung function (FEV1). Thirty-four out of 70 patients (48.57%) fulfilled the criteria of super-responder, and 17 out of 70 (24.29%) had a complete response. More patients in the group with nasal polyps fulfilled the criteria of super-responder and complete response to mepolizumab. CONCLUSIONS: Mepolizumab is a safe and effective treatment for SEA patients, improving exacerbations, oral corticosteroid intake, asthma control, quality of life, and lung function. In patients with associated nasal polyposis, there is a statistically significant higher proportion of super-responders and complete responders.

4-Octyl Itaconate Alleviates Airway Eosinophilic Inflammation by Suppressing Chemokines and Eosinophil Development.

4-Octyl itaconate (4-OI) is a derivative of the Krebs cycle-derived metabolite itaconate and displays an array of antimicrobial and anti-inflammatory properties through modifying cysteine residues within protein targets. We have found that 4-OI significantly reduces the production of eosinophil-targeted chemokines in a variety of cell types, including M1 and M2 macrophages, Th2 cells, and A549 respiratory epithelial cells. Notably, the suppression of these chemokines in M1 macrophages was found to be NRF2-dependent. In addition, 4-OI can interfere with IL-5 signaling and directly affect eosinophil differentiation. In a model of eosinophilic airway inflammation in BALB/c mice, 4-OI alleviated airway resistance and reduced eosinophil recruitment to the lungs. Our findings suggest that itaconate derivatives could be promising therapeutic agents for the treatment of eosinophilic asthma.

Cost-effectiveness and resource use analysis of patients with asthma before and after treatment with mepolizumab in a real-life setting.

OBJECTIVE: To define the cost-effectiveness and health resource use of mepolizumab in a cohort of patients with severe eosinophilic asthma in real-life conditions in Spain. METHODS: This was an observational, retrospective, single-center study. Patients included were diagnosed with severe eosinophilic asthma and treated with mepolizumab 100 mg subcutaneous (SC) 4-weekly for 12 months. Outcomes evaluated: incremental cost-effectiveness ratio (ICER), number of exacerbations, disease control with the Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), and direct and indirect cost per patient. RESULTS: 12 months after mepolizumab initiation, a significant decrease in exacerbations was shown, from a mean (standard deviation [SD]) of 3.1 (2.6) to 0.7 (1.5), an increase from 4.9 (0.4) to 6.1 (0.5) in AQLQ, and from 14.9 (5.7) to 21.5 (3.9) in ACT scores. The number of cortico-dependent patients significantly decreased from 53.3% to 13.3% during this period. There was a significant decrease of 94% in the cost of hospitalization, from a mean (SD) of €4063.9 (5423.9) pretreatment to €238.6 (1306.9) post-treatment (p = 0.0003). Total costs decreased significantly from a median of €2,423.1 (1,512.8; 9,320.9) pretreatment to €1,177.5 (965.0; 1,737.8) post-treatment if mepolizumab was excluded. ICER per exacerbation avoided was €3606.9, per 3-point ACT score increase €3934.8, and per 0.5-point AQLQ score increase €3606.9. CONCLUSIONS: Mepolizumab improves control of asthma and quality of life in patients with severe diseases in a cost-effectiveness range. The number of exacerbations decreased, and there was a clear reduction in primary care visits and hospitalizations. Further economic analyses of biological therapies for asthma are required.

Safety and efficacy of benralizumab in elderly subjects with severe asthma.

INTRODUCTION: The prevalence of asthma in adults >65 years old is approximately 12-14%, and 10% have severe asthma. A higher mortality rate is observed in subjects with asthma >65 years old and especially >80 years old. OBJECTIVE: To analyze the effectiveness and safety of at least three doses of benralizumab in a subgroup of elderly subjects (>65 years old) with uncontrolled severe eosinophilic asthma in real-life conditions. METHODS: This was a retrospective multicenter study (AUTOBENRA study) conducted in 9 hospitals that included 72 patients aged >18 years old with uncontrolled severe asthma based on the Spanish Asthma Guidelines who were treated with at least three doses of benralizumab, self-administered at home since before April 30, 2021. The recruitment period ended on October 1, 2021. Written consent was obtained before the study commencement. In this subanalysis, we compared the results between patients >65 years old and patients <65 years old. RESULTS: A total of 72 subjects with severe asthma were screened, and 54 were included (MD: 57.3 ± 10 years old). There were 12 subjects aged >65 years old [MD: 69.8 ± 4.3 years old (minimum: 65 years old; maximum: 83 years old)]. Subjects >65 years old experienced statistically significant improvement in lung function, ACT and mini-AQLQ with benralizumab. Additionally, 9 patients (75%) experienced no asthma exacerbation (p = 0.0047), half (3/6) were able to stop OCS (p = 0.08), and no adverse effects with benralizumab were reported during the 20 months of follow-up. CONCLUSIONS: In patients aged >65 years old, benralizumab was an effective and safe therapy for severe eosinophilic asthma in our study, with no significant differences from the younger subgroup. This is especially important since they are a group with numerous comorbidities, medications and worse quality of life.

Long-term use of mepolizumab in a case of chronic eosinophilic pneumonia: extending interval dosing.

INTRODUCTION: Mepolizumab, a humanized anti IL-5 monoclonal antibody, has been used off-label for chronic eosinophilic pneumonia (CEP), inducing disease remission and saving systemic corticosteroids. CASE STUDY: We present a case of CEP, requiring long-term corticosteroids therapy due to relapse upon withdrawal. Mepolizumab was started and maintained for 2 years and 6 months. RESULTS: Corticosteroids could be withdrawn and mepolizumab dose interval was spared up to 10 wk with no disease relapse. CONCLUSION: Mepolizumab is shown to be useful for chronic eosinophilic pneumonia, allowing corticosteroid withdrawal. Dose interval may be individualized under close monitoring, for a more efficient treatment, reducing medical costs while improving patients' quality of life.

Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.