Eosinophilic and Noneosinophilic Asthma: An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort.

BACKGROUND: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. RESEARCH QUESTION: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? STUDY DESIGN AND METHODS: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). RESULTS: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. INTERPRETATION: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.

Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial.

BACKGROUND: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. METHODS: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18-75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per µL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. FINDINGS: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39-0·65; p<0·0001) over the 24-week treatment period and provided clinically meaningful and statistically significant improvement from baseline to week 24 in SGRQ total score versus placebo (least squares mean change from baseline -8·11 (95% CI -11·41 to -4·82; p<0·0001), with similar differences at earlier timepoints. Benralizumab improved FEV1, PEF, ACQ-6, CGI-C, PGI-C, PSIA, and SNOT-22 at week 24 versus placebo, with differences observed early (within weeks 1 to 4). Adverse events were reported for 271 (63%) of 427 patients on benralizumab versus 143 (62%) of 229 patients on placebo. The most commonly reported adverse events for the 427 patients receiving benralizumab (frequency >5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. INTERPRETATION: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. FUNDING: AstraZeneca.

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab.

Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety. Eosinophils have been associated with host protection and tumor growth, raising potential concerns about the consequences of long-term therapies that deplete eosinophils. However, evidence for these associations in humans is conflicting and largely indirect or based on mouse models. Substantial prospective clinical trial and postmarketing data have accrued, providing insight into the potential risks associated with eosinophil depletion. In this review, we explore the current safety profile of eosinophil-reducing therapies, with particular attention to the potential risks of malignancies and severe infections and a focus on benralizumab. Benralizumab is an IL-5Rα-directed cytolytic monoclonal antibody that targets and efficiently depletes blood and tissue eosinophils through antibody-dependent cell-mediated cytotoxicity. Benralizumab is intended to treat patients with severe, uncontrolled asthma with eosinophilic inflammation. The integrated analyses of benralizumab safety data from the phase III SIROCCO and CALIMA trials and subsequent BORA extension trial for patients with asthma, and the phase III GALATHEA and TERRANOVA trials for patients with chronic obstructive pulmonary disease, form the principal basis for this review.

Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma.

Benralizumab is an anti-eosinophilic monoclonal antibody that reduces exacerbations and improves lung function for patients with severe, uncontrolled asthma with eosinophilic inflammation. We evaluated the impact of baseline factors on benralizumab efficacy for patients with severe asthma.This analysis used pooled data from the SIROCCO (ClinicalTrials.gov identifier NCT01928771) and CALIMA (ClinicalTrials.gov identifier NCT01914757) Phase III studies. Patients aged 12-75 years with severe, uncontrolled asthma receiving high-dosage inhaled corticosteroids plus long-acting ß2-agonists received benralizumab 30 mg subcutaneously every 8 weeks (Q8W, first three doses every 4 weeks (Q4W)), Q4W or placebo. Baseline factors that influenced benralizumab efficacy were evaluated, including oral corticosteroid (OCS) use, nasal polyposis, pre-bronchodilator forced vital capacity (FVC), prior year exacerbations and age at diagnosis. Efficacy outcomes included annual exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s at treatment end relative to placebo.Benralizumab Q8W treatment effect was enhanced with each baseline factor for all patients and those with ≥300 eosinophils·µL-1 relative to the overall population. OCS use, nasal polyposis and FVC <65% of predicted were associated with greater benralizumab Q8W responsiveness for reduced exacerbation rate for patients with <300 eosinophils·µL-1Baseline clinical factors and blood eosinophil counts can help identify patients potentially responsive to benralizumab.

Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.

BACKGROUND: In placebo-controlled trials, reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. OBJECTIVE: This open-label extension study evaluated safety and efficacy of reslizumab for up to 24 months. METHODS: After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. RESULTS: In the open-label extension, 1,051 patients received ≥1 reslizumab dose (480 reslizumab-naïve, 571 reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in reslizumab-naïve and reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after reslizumab discontinuation. CONCLUSIONS: In patients with moderate-to-severe eosinophilic asthma, intravenous reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies.

Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study.

BACKGROUND: This phase 3 study further characterizes the efficacy and safety of reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/µL. METHODS: Patients were randomized to receive reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV1 over 16 weeks. Secondary end points included FVC, forced expiratory flow at 25% to 75% of FVC (FEF25%-75%), patient-reported control of asthma symptoms, short-acting ß-agonist (SABA) use, blood eosinophil levels, and safety. RESULTS: Reslizumab significantly improved FEV1 (difference vs placebo [reslizumab 0.3 and 3.0 mg/kg], 115 mL [95% CI, 16-215; P = .0237] and 160 mL [95% CI, 60-259; P = .0018]). Clinically meaningful increases in FVC (130 mL) and FEF25%-75% (233 mL/s) were observed with reslizumab 3.0 mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vs placebo (greater effects seen with 3.0 mg/kg; P < .05). The minimally important difference was reached for the AQLQ (reslizumab 3.0 mg/kg) but not on the ACQ. Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab. The most common adverse events were worsening of asthma, headache, and nasopharyngitis; most events were mild to moderate in severity. CONCLUSIONS: Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose, with comparable safety. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.

Left ventricular intracardiac metastatic germ cell tumor presenting with hemorrhagic cerebrovascular event.

We describe an unusual case of a 26-year-old man admitted with respiratory distress and found to have testicular cancer metastatic to the lung and heart. Twelve days after admission, the patient experienced multiple hemorrhagic strokes. Echocardiography demonstrated testicular cancer metastatic to the septal surface of the left ventricle of the heart with presumed embolization to the cerebrovascular region. The patient received chemotherapy and radiation therapy to the areas of tumor mass with subsequent resolution of tumor burden. This is the first reported case of metastasis from embryonal carcinoma of the testis to the left ventricle of the heart.

TRAIL in the airways.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is an important immunomodulatory factor that may play a role in the structural changes observed in the asthmatic airways. In vitro as well as in vivo studies have evidenced a dual role for TRAIL: it can either function as a pro- or anti-inflammatory cytokine on inflammatory cells, participating in the initiation and resolution of inflammatory and immune responses. TRAIL is expressed in the airways by inflammatory cells infiltrated in the bronchial mucosa, as well as by structural cells of the airway wall including fibroblasts, epithelial, endothelial, and smooth muscle cells. By releasing TRAIL, these different cell types may then participate in the increased levels of TRAIL observed in bronchoalveolar lavage fluid from asthmatic patients. Taken together, this suggests that TRAIL may play a role in inflammation in asthma. However, concerning its role is dual in the modulation of inflammation, further studies are needed to elucidate the precise role of TRAIL in the airways.

Differential expression of TRAIL and TRAIL receptors in allergic asthmatics following segmental antigen challenge: evidence for a role of TRAIL in eosinophil survival.

Asthma is a chronic lung disease exhibiting airway obstruction, hyperresponsiveness, and inflammation, characterized by the infiltration of eosinophils into the airways and the underlying tissue. Prolonged eosinophilic inflammation depends on the balance between the cell's inherent tendency to undergo apoptosis and the local eosinophil-viability enhancing activity. TRAIL, a member of the TNF family, induces apoptosis in most transformed cells; however, its role in health and disease remains unknown. To test the hypothesis that Ag-induced inflammation is associated with TRAIL/TRAIL-R interactions, we used a segmental Ag challenge (SAC) model in ragweed-allergic asthmatics and nonasthmatic patients and analyzed bronchoalveolar lavage (BAL) material for 2 wk. In asthmatic patients, the level of TRAIL in BAL fluid dramatically increased 24 h after SAC, which significantly correlated with BAL eosinophil counts. Immunohistochemical analysis of bronchial biopsies from asthmatic patients demonstrated that TRAIL staining was increased in epithelial, airway smooth muscle, and vascular smooth muscle cells and throughout the interstitial tissue after SAC. This was confirmed by quantitative immunocytochemical image analysis of BAL eosinophils and alveolar macrophages, which demonstrated that expression levels of TRAIL and DcR2 increased, whereas expression levels of the TRAIL-Rs DR4 and DR5 decreased in asthmatic subjects after SAC. We also determined that TRAIL prolongs eosinophil survival ex vivo. These data provide the first in vivo evidence that TRAIL expression is increased in asthmatics following Ag provocation and suggest that modulation of TRAIL and TRAIL-R interactions may play a crucial role in promoting eosinophil survival in asthma.

Asthmatic epithelial cell proliferation and stimulation of collagen production: human asthmatic epithelial cells stimulate collagen type III production by human lung myofibroblasts after segmental allergen challenge.

Epithelial injury and subepithelial collagen deposition are characteristic of asthma. We hypothesized that epithelial cell proliferation increases after airway injury in asthmatics, that epithelial cells stimulate lung myofibroblast collagen production, and that both processes are modulated by allergen-recruited inflammatory cells. Epithelial cells obtained at baseline, 1 d, and 1 and 2 wk after endobronchial allergen challenge from asthmatics and nonasthmatics were placed in culture, with and without bronchoalveolar lavage cells obtained from the same segment. Epithelial cell proliferation and collagen synthesis by human lung myofibroblasts stimulated with culture medium from these epithelial cells were determined. Epithelial proliferation increased (108 +/- 50% above baseline, p = 0.01 for d, and p = 0.004 for group x day interaction) 1 wk postchallenge in cells from asthmatics, but not from nonasthmatics, and required bronchoalveolar lavage cell coculture. Culture medium from epithelium harvested from asthmatics, but not from nonasthmatics, at 1 to 2 wk postchallenge stimulated collagen type III production 50% to 70% (p = 0.043 for clinical group, p = 0.012 for day, and p = 0.022 for group x day interaction), but not collagen type I. This effect was independent of an acute eosinophilic response. We conclude that epithelial cells from asthmatics, but not from nonasthmatics, are stimulated to proliferate after allergen challenge, and over 1 to 2 wk postchallenge, stimulate collagen type III synthesis by lung myofibroblasts. Epithelial cell proliferation appears dependent upon infiltrating inflammatory cells, but stimulation of collagen type III does not.