Ana R. Sousa

Mepolizumab and exacerbations of refractory eosinophilic asthma.

BACKGROUND Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)

Mepolizumab, a humanized anti–IL-5 mAb, as a treatment option for severe nasal polyposis

BACKGROUND Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI)

Patients with severe refractory asthma pose a major healthcare problem. Over the last decade it has become increasingly clear that, for the development of new targeted therapies, there is an urgent need for further characterisation and classification of these patients. The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium is a pan-European public-private collaboration funded by the European Commission Innovative Medicines Initiative of the European Union. U-BIOPRED aims to subphenotype patients with severe refractory asthma by using an innovative systems biology approach. This paper presents the U-BIOPRED international consensus on the definition and diagnosis of severe asthma, aligning the latest concepts in adults as well as in children. The consensus is based on existing recommendations up to 2010 and will be used for the selection of patients for the upcoming U-BIOPRED study. It includes the differentiation between ‘problematic’, ‘difficult’ and ‘severe refractory’ asthma, and provides a systematic algorithmic approach to the evaluation of patients presenting with chronic severe asthma symptoms for use in clinical research and specialised care.

External validation of blood eosinophils, FE NO and serum periostin as surrogates for sputum eosinophils in asthma

Background Monitoring sputum eosinophils in asthma predicts exacerbations and improves management of asthma. Thus far, blood eosinophils and FENO show contradictory results in predicting eosinophilic airway inflammation. More recently, serum periostin was proposed as a novel biomarker for eosinophilic inflammation. Objectives Quantifying the mutual relationships of blood eosinophils, FENO, and serum periostin with sputum eosinophils by external validation in two independent cohorts across various severities of asthma. Methods The first cohort consisted of 110 patients with mild to moderate asthma (external validation cohort). The replication cohort consisted of 37 patients with moderate to severe asthma. Both cohorts were evaluated cross-sectionally. Sputum was induced for the assessment of eosinophils. In parallel, blood eosinophil counts, serum periostin concentrations and FENO were assessed. The diagnostic accuracy of these markers to identify eosinophilic asthma (sputum eosinophils ≥3%) was calculated using receiver operating characteristics area under the curve (ROC AUC). Results In the external validation cohort, ROC AUC for blood eosinophils was 89% (p<0.001) and for FENO level 78% (p<0.001) to detect sputum eosinophilia ≥3%. Serum periostin was not able to distinguish eosinophilic from non-eosinophilic airway inflammation (ROC AUC=55%, p=0.44). When combining these three variables, no improvement was seen. The diagnostic value of blood eosinophils was confirmed in the replication cohort (ROC AUC 85%, p<0.001). Conclusions In patients with mild to moderate asthma, as well as patients with more severe asthma, blood eosinophils had the highest accuracy in the identification of sputum eosinophilia in asthma. The use of blood eosinophils can facilitate individualised treatment and management of asthma. Trial registration NTR1846 and NTR2364.

Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach. This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements. Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids. Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach. Severe asthma results in more airway inflammation, worse symptoms and lower lung function, despite increased therapy http://ow.ly/QznR3

Elevated Sputum Interleukin-5 and Submucosal Eosinophilia in Obese Individuals with Severe Asthma

RATIONALE The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.

In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation

BACKGROUND Corticosteroid-resistant (CR) asthma is associated with increased in vitro activity of the proinflammatory transcription factor activating peptide (AP)-1 in PBMCs resulting from increased c-FOS synthesis. Increased AP-1 may sequester the glucocorticoid receptor to produce a CR state. Using the tuberculin-induced inflammatory responses in the skin, we have previously demonstrated that a therapeutically effective dose of prednisolone suppressed T-cell, macrophage, and eosinophil infiltration into purified protein derivative-induced lesional skin of corticosteroid-sensitive (CS), but not CR, individuals. OBJECTIVE Skin biopsy specimens from a tuberculin-induced model of dermal inflammation have been evaluated for the effect of corticosteroids in regulating components of AP-1 in vivo. METHODS Immunohistochemical analysis of the tuberculin-mediated cutaneous response has been performed on 9 subjects with CS asthma and 6 subjects with CR asthma for the regulatory components of AP-1 before and after 9 days of either 40 mg prednisolone or placebo. RESULTS Significantly greater expression of c-FOS, phosphorylated c-JUN, and phosphorylated JUN N-terminal kinase (JNK) protein has been identified in CR than in CS subjects. Corticosteroids suppressed phosphorylation of c-JUN and JNK in the CS Group (P =.004 for both) but enhanced phosphorylation of c-JUN and JNK in the CR group (P =.031 for both). CONCLUSION Resistance to corticosteroids in asthmatic subjects may be caused, at least in part, by failure to suppress JNK phosphorylation, leading to failure to suppress c-JUN N-phosphorylation. Increased JNK may be one of the mechanisms central to the mechanism of CR asthma.

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life http://ow.ly/RrrGE

Effect of endobronchial aspirin challenge on inflammatory cells in bronchial biopsy samples from aspirin-sensitive asthmatic subjects.

BACKGROUND: The aspirin-induced bronchoconstriction in patients with aspirin-sensitive asthma is caused by cysteinyl leukotriene release. The cellular source of the leukotrienes is unknown. The inflammatory cell infiltrate in bronchial biopsy samples from seven aspirin-sensitive asthmatic (ASA) subjects and eight non-ASA subjects before and after local challenge with lysine aspirin was therefore examined. METHODS: Using flexible bronchoscopy, airway mucosal biopsy samples were taken and lysine aspirin solution was placed directly onto a carina of the contralateral lung. Twenty minutes later a second series of biopsy samples was taken from the site of the local endobronchial lysine aspirin challenge. The biopsy samples were double immunostained with a rabbit polyclonal antibody to the enzyme 5-lipoxygenase and monoclonal antibodies to mast cells (AA1), neutrophils (NP57), macrophages (EBM11), T lymphocytes (anti-CD3), and total (BMK13) and activated eosinophils (EG2). RESULTS: A decrease in both absolute mast cell numbers staining with mast cell tryptase (AA1) and the percentage of mast cells co-immunostaining with 5-lipoxygenase was seen in the ASA patients after lysine aspirin challenge compared with the non-ASA control group. There was also an increase in the numbers of activated eosinophils (EG2) in the ASA subjects compared with the non-ASA group. No changes were observed in the total numbers of macrophages (EBM11), neutrophils (NP57), total eosinophils (BMK13), and T lymphocytes (anti-CD3) after challenge with lysine aspirin. CONCLUSIONS: The decrease in numbers of mast cells staining for tryptase and the increase in activated eosinophils after endobronchial challenge with lysine aspirin may represent degranulation of these cell types, and may be an early event associated with aspirin-sensitive reactions in ASA subjects.

Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial

Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor.