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.

Achieving clinical outcomes with benralizumab in severe eosinophilic asthma patients in a real-world setting: orbe II study.

BACKGROUND: The ORBE II study aimed to describe the characteristics and clinical outcomes of adult patients with severe eosinophilic asthma (SEA) treated with benralizumab in a real-world setting in Spain. METHODS: ORBE II (NCT04648839) was an observational, retrospective cohort study in adult SEA patients who had been prescribed benralizumab. Demographic and clinical data of 204 SEA patients were collected 12 months prior to benralizumab initiation (baseline) and at follow-up. Exacerbation rate, asthma symptoms, maintenance oral corticosteroid (OCS) use and lung function were evaluated, among other variables. RESULTS: A total of 204 SEA patients were evaluated. Mean (standard deviation, SD) age of the study population was 56.4 (12.4) years, 62.3% were women and mean (SD) duration of asthma was 15.1 (12.7) years. Median (Q1-Q3) follow-up duration was 19.5 (14.2-24.2) months. At baseline, 72.6% of the overall population (OP) presented blood eosinophil counts ≥ 300 cells/µL; 36.8% had comorbid chronic rhinosinusitis with nasal polyps (CRSwNP); 84.8% reported at least one severe exacerbation, and 29.1% were OCS-dependent. At 1 year of follow-up, patients receiving benralizumab treatment had a 85.6% mean reduction in exacerbations from baseline, and 81.4% of patients achieved zero exacerbations. We also found a clinically relevant mean (SD) increase in pre-bronchodilator (BD) FEV1 of 331 (413) mL, with 66.7% of patients achieving a pre-BD FEV1 increase ≥ 100 mL, and 46.3% of patients achieving a pre-BD FEV1 ≥ 80% of predicted. Regarding symptom control, 73.8% of the OP obtained an ACT score ≥ 20 points. After 1 year of follow-up, mean reduction in the daily OCS dose was 70.5%, and complete OCS withdrawal was achieved by 52.8% of the OCS-dependent patients. Almost half (43.7%) of the OP on benralizumab met all four criteria for clinical remission. Patients with concomitant CRSwNP obtained similar or enhanced outcomes. CONCLUSIONS: These data support the real-world benefits of benralizumab in SEA patients, and particularly in those with concomitant CRSwNP. TRIAL REGISTRATION: NCT04648839.

Obese Asthma Phenotype Is Associated with hsa-miR-26a-1-3p and hsa-miR-376a-3p Modulating the IGF Axis.

Clarifying inflammatory processes and categorising asthma into phenotypes and endotypes improves asthma management. Obesity worsens severe asthma and reduces quality of life, although its specific molecular impact remains unclear. We previously demonstrated that hsa-miR-26a-1-3p and hsa-miR-376a-3p, biomarkers related to an inflammatory profile, discriminate eosinophilic from non-eosinophilic asthmatics. We aimed to study hsa-miR-26a-1-3p, hsa-miR-376a-3p, and their target genes in asthmatic subjects with or without obesity to find biomarkers and comprehend obese asthma mechanisms. Lung tissue samples were obtained from asthmatic patients (n = 16) and healthy subjects (n = 20). We measured miRNA expression using RT-qPCR and protein levels (IGF axis) by ELISA in confirmation samples from eosinophilic (n = 38) and non-eosinophilic (n = 39) obese (n = 26) and non-obese (n = 51) asthma patients. Asthmatic lungs showed higher hsa-miR-26a-1-3p and hsa-miR-376a-3p expression than healthy lungs. A study of seven genes regulated by these miRNAs revealed differential expression of IGFBP3 between asthma patients and healthy individuals. In obese asthma patients, we found higher hsa-miR-26a-1-3p and IGF-1R values and lower values for hsa-miR-376a-3p and IGFBP-3. Hsa-miR-26a-1-3p and IGFBP-3 were directly and inversely correlated with body mass index, respectively. Hsa-miR-26a-1-3p and hsa-miR-376a-3p could be used as biomarkers to phenotype patients with eosinophilic and non-eosinophilic asthma in relation to comorbid obesity.

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids.

Nowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.

Changes in Serum MicroRNAs after Anti-IL-5 Biological Treatment of Severe Asthma.

There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which function as very important elements in intercellular communication. They are capable of distributing genetic material, mRNA, mitochondrial DNA, and microRNAs (miRNAs). Serum miRNA screening was performed in order to analyze possible changes in serum miRNAs in 10 patients treated with reslizumab and 6 patients with mepolizumab after 8 weeks of treatment. The expression of miR-338-3p was altered after treatment (p < 0.05), although no significant differences between reslizumab and mepolizumab were found. Bioinformatic analysis showed that miR-338-3p regulates important pathways in asthma, such as the MAPK and TGF-ß signaling pathways and the biosynthesis/degradation of glucans (p < 0.05). However, it did not correlate with an improvement in lung function. MiRNA-338-3p could be used as a biomarker of early response to reslizumab and mepolizumab in severe eosinophilic asthmatic patients. In fact, this miRNA could be involved in airway remodeling, targeting genes related to MAPK and TGF-ß signaling pathways.

Histiocytic hyperplasia with hemophagocytosis and acute alveolar damage in COVID-19 infection.

The spectrum of COVID-19 infection includes acute respiratory distress syndrome (ARDS) and macrophage activation syndrome (MAS), although the histological basis for these disorders has not been thoroughly explored. Post-mortem pulmonary and bone marrow biopsies were performed in 33 patients. Samples were studied with a combination of morphological and immunohistochemical techniques. Bone marrow studies were also performed in three living patients. Bone marrow post-mortem studies showed striking lesions of histiocytic hyperplasia with hemophagocytosis (HHH) in most (16/17) cases. This was also observed in three alive patients, where it mimicked the changes observed in hemophagocytic histiocytosis. Pulmonary changes included a combination of diffuse alveolar damage with fibrinous microthrombi predominantly involving small vessels, in particular the alveolar capillary. These findings were associated with the analytical and clinical symptoms, which helps us understand the respiratory insufficiency and reveal the histological substrate for the macrophage activation syndrome-like exhibited by these patients. Our results confirm that COVID-19 infection triggers a systemic immune-inflammatory disease and allow specific therapies to be proposed.

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.

Comparison of Long-term Response and Remission to Omalizumab and Anti-IL-5/IL-5R Using Different Criteria in a Real-life Cohort of Severe Asthma Patients.

BACKGROUND: Evaluation of biologic therapy response is vital to monitor its effectiveness. Authors have proposed various response criteria including good responder, super-responder, non-responder, and clinical remission. OBJECTIVES: To ascertain the prevalence of response and clinical remission after long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics, compare these results with existing criteria, and identify predictors for non-responders and clinical remission. METHODS: A multicenter, real-life study involving severe asthma patients in Spain. Various outcomes were assessed to gauge response and clinical remission against established criteria. RESULTS: The study included 429 patients, 209 (48.7%) omalizumab, 112 (26.1%) mepolizumab, 19 (4.4%) reslizumab and 89 (20.7%) benralizumab, with a mean treatment duration of 55.3±38.8 months. In the final year of treatment, 218 (50.8%) were super-responders, 173 (40.3%) responders, 38 (8.9%) non-responders, and clinical remission in 116 (27%), without differences among biologics. The short-term non-responders (<6 months) were 25/545 (4.6%). Substantial variations in response and clinical remission were observed when applying different published criteria. Predictors of non-response included higher BMI (OR:1.14; 95% CI:1.06-1.23; p<0.001), admissions at ICU (2.69; 1.30-5.56; p=0.01), high count of SAE (1.21; 1.03-1.42; p=0.02) before biologic treatment. High FEV1% (0.96; 0.95-0.98; p<0.001), a high ACT score (0.93; 0.88-0.99; p=0.01) before biologic treatment or NSAID-ERD (0.52; 0.29-0.91; p=0.02) showed strong associations with achieving clinical remission. CONCLUSION: A substantial proportion of severe asthma patients treated long-term with omalizumab or anti-IL5/IL-5Rα achieved a good response. Differences in response criteria highlight the need for harmonization in defining response and clinical remission in biologic therapy to enable meaningful cross-study comparisons.

Identification of Asthma Phenotypes in the Spanish MEGA Cohort Study Using Cluster Analysis.

INTRODUCTION: The definition of asthma phenotypes has not been fully established, neither there are cluster studies showing homogeneous results to solidly establish clear phenotypes. The purpose of this study was to develop a classification algorithm based on unsupervised cluster analysis, identifying clusters that represent clinically relevant asthma phenotypes that may share asthma-related outcomes. METHODS: We performed a multicentre prospective cohort study, including adult patients with asthma (N=512) from the MEGA study (Mechanisms underlying the Genesis and evolution of Asthma). A standardised clinical history was completed for each patient. Cluster analysis was performed using the kernel k-groups algorithm. RESULTS: Four clusters were identified. Cluster 1 (31.5% of subjects) includes adult-onset atopic patients with better lung function, lower BMI, good asthma control, low ICS dose, and few exacerbations. Cluster 2 (23.6%) is made of adolescent-onset atopic asthma patients with normal lung function, but low adherence to treatment (59% well-controlled) and smokers (48%). Cluster 3 (17.1%) includes adult-onset patients, mostly severe non-atopic, with overweight, the worse lung function and asthma control, and receiving combination of treatments. Cluster 4 (26.7%) consists of the elderly-onset patients, mostly female, atopic (64%), with high BMI and normal lung function, prevalence of smokers and comorbidities. CONCLUSION: We defined four phenotypes of asthma using unsupervised cluster analysis. These clusters are clinically relevant and differ from each other as regards FEV1, age of onset, age, BMI, atopy, asthma severity, exacerbations, control, social class, smoking and nasal polyps.

Disposition of Work-Related Asthma in a Spanish Asthma Cohort: Comparison of Asthma Severity Between Employed and Retired Workers.

BACKGROUND: Exposure to certain agents in the workplace can trigger occupational asthma or work-exacerbated asthma, both of which come under the heading of work-related asthma (WRA). Understanding the burden that WRA represents can help in the management of these patients. OBJECTIVE: To assess the influence of occupation on asthma in real life and analyze the characteristics of patients with WRA included in an asthma cohort. METHODS: This was a prospective multicenter study of a cohort of consecutive patients with asthma. A standardized clinical history was completed. Patients were classified as having WRA or non-WRA. All patients underwent respiratory function tests, FeNO test, and methacholine challenge (methacholine concentration that causes a 20% drop in FEV1) at the beginning of the study. They were classified into two groups, depending on their employment status: employed (group 1) or unemployed (group 2). RESULTS: Of the 480 patients included in the cohort, 82 (17%) received the diagnosis of WRA. Fifty-seven patients (70%) were still working. Mean age (SD) was 46 (10.69) years in group 1 and 57 (9.91) years in group 2 (P < .0001). Significant differences were observed in adherence to treatment (64.9% in group 1 vs 88% in group 2; P = .0354) and in severe asthma exacerbations (35.7% in group 1 vs 0% in group 2; P = .0172). No significant differences were observed in the rest of the variables analyzed. CONCLUSIONS: The burden of WRA in specialized asthma units is not negligible. The absence of differences in the severity of asthma, the treatment administered, alterations in lung function, and the number of exacerbations in those working versus not working may support the idea that advice regarding changing jobs should be customized for individual patients.

miR-144-3p Is a Biomarker Related to Severe Corticosteroid-Dependent Asthma.

MicroRNAs are non-coding molecules that act both as regulators of the epigenetic landscape and as biomarkers for diseases, including asthma. In the era of personalized medicine, there is a need for novel disease-associated biomarkers that can help in classifying diseases into phenotypes for treatment selection. Currently, severe eosinophilic asthma is one of the most widely studied phenotypes in clinical practice, as many patients require higher and higher doses of corticosteroids, which in some cases fail to achieve the desired outcome. Such patients may only benefit from alternative drugs such as biologics, for which novel biomarkers are necessary. The objective of the study was to study the expression of miR-144-3p in order to discover its possible use as a diagnostic biomarker for severe asthma. For this purpose, miR-144-3p was evaluated in airway biopsies and serum from asthmatics and healthy individuals. mRNA was studied in asthmatic biopsies and smooth muscle cells transfected with miR-144-3p mimic. An in silico regulation of miR-144-3p was performed using miRSystem, miRDB, STRING, and ShinyGO for pathway analysis. From our experimental procedures, we found that miR-144-3p is a biomarker associated with asthma severity and corticosteroid treatment. MiR-144-3p is increased in asthmatic lungs, and its presence correlates directly with blood eosinophilia and with the expression of genes involved in asthma pathophysiology in the airways. When studied in serum, this miRNA was increased in severe asthmatics and associated with higher doses of corticosteroids, thereby making it a potential biomarker for severe asthma previously treated with higher doses of corticosteroids. Thus, we can conclude that miR-144-3p is associated with severe diseases in both the airways and serum of asthmatics, and this association is related to corticosteroid treatment.

Reliability, Satisfaction and Effectiveness of Benralizumab Home Self-Administration in Patients with Severe Eosinophilic Asthma in Real-World Practice: The Auto-Benra Study.

Introduction: The increase in drugs available for severe uncontrolled asthma and the lifestyle of these patients make it necessary to implement self-administration programs of these therapies at home. Benralizumab, a monoclonal antibody targeting IL5R, was authorized in Spain for poorly controlled severe eosinophilic asthma. The possibility of administration at home was approved in March 2020 in Spain. The aim of the Auto-Benra study was to evaluate the usability and satisfaction of the benralizumab prefilled syringe and autoinjector and assessing the effectivity of these devices in uncontrolled severe eosinophilic asthma (SEA) in home-self administration. Methods: This is a retrospective, observational multicenter study uncontrolled SEA patients treated with benralizumab at least with 3 doses self-administered at home before April 30, 2021. Reliability and satisfaction with benralizumab at home were evaluated with subcutaneous administration assessment questionnaire (SQAAQ) and visual analogic scales (VAS). Effectiveness was evaluated in all patients with asthma control test (ACT), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), annual exacerbation rate, oral corticosteroid treatment (OCS) and asthma-related hospitalizations and emergency visits. Results: Fifty-four patients across 9 hospitals in Spain were included. The mean SQAAQ score was 6.89 (±0.16) points. Patients and their caregivers and doctors report excellent satisfaction by VAS, with no differences between benralizumab devices used (prefilled syringe and autoinjector). Severe exacerbation rate decreased by 65% (p = 0.0007) after benralizumab treatment. ACT score improved on average 6.27 ± 5.35 points (p < 0.0001) and the mean MiniAQLQ increased up to 1.58 ± 1.47 points (p < 0.0001). Twenty-four patients were OCS-dependent and at the end of study 14 patients get complete OCS withdrawal. Conclusion: AUTO-BENRA study supports the use of benralizumab at home given the excellent results of satisfaction and usability by patients and their caregivers.

How reliably can algorithms identify eosinophilic asthma phenotypes using non-invasive biomarkers?

Background and Aims: Asthma is a heterogeneous respiratory disease that encompasses different inflammatory and functional endophenotypes. Many non-invasive biomarkers has been investigated to its pathobiology. Heany et al proposed a clinical algorithm that classifies severe asthmatic patients into likely-eosinophilic phenotypes, based on accessible biomarkers: PBE, current treatment, FeNO, presence of nasal polyps (NP) and age of onset. Materials and Methods: We assessed the concordance between the algorithm proposed by Heany et al. with sputum examination, the gold standard, in 145 asthmatic patients of the MEGA cohort with varying grades of severity. Results: No correlation was found between both classifications 0.025 (CI = 0.013-0.037). Moreover, no relationship was found between sputum eosinophilia and peripheral blood eosinophilia count in the total studied population. Discussion and Conclusion: In conclusion, our results suggest that grouping the biomarkers proposed by Heany et al. are insufficient to diagnose eosinophilic phenotypes in asthmatic patients. Sputum analysis remains the gold standard to assess airway inflammation.

Eosinophils and Chronic Respiratory Diseases in Hospitalized COVID-19 Patients.

BACKGROUND: Studies on the role of eosinophils in coronavirus disease 2019 (COVID-19) are scarce, though available findings suggest a possible association with disease severity. Our study analyzes the relationship between eosinophils and COVID-19, with a focus on disease severity and patients with underlying chronic respiratory diseases. METHODS: We performed a retrospective analysis of 3018 subjects attended at two public hospitals in Madrid (Spain) with PCR-confirmed SARS-CoV-2 infection from January 31 to April 17, 2020. Patients with eosinophil counts less than 0.02×109/L were considered to have eosinopenia. Individuals with chronic respiratory diseases (n=384) were classified according to their particular underlying condition, i.e., asthma, chronic pulmonary obstructive disease, or obstructive sleep apnea. RESULTS: Of the 3018 patients enrolled, 479 were excluded because of lack of information at the time of admission. Of 2539 subjects assessed, 1396 patients presented an eosinophil count performed on admission, revealing eosinopenia in 376 cases (26.93%). Eosinopenia on admission was associated with a higher risk of intensive care unit (ICU) or respiratory intensive care unit (RICU) admission (OR:2.21; 95%CI:1.42-3.45; p<0.001) but no increased risk of mortality (p>0.05). CONCLUSIONS: Eosinopenia on admission conferred a higher risk of severe disease (requiring ICU/RICU care), but was not associated with increased mortality. In patients with chronic respiratory diseases who develop COVID-19, age seems to be the main risk factor for progression to severe disease or death.

Serum microRNAs as Tool to Predict Early Response to Benralizumab in Severe Eosinophilic Asthma.

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.