Guy Brusselle

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

BACKGROUND Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. Georges Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV1/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV1 (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 × 10−8) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

Attenuation of allergic airway inflammation in IL‐4 deficient mice

To investigate the role of IL‐4 in vivo in allergic asthma, we developed a murine model of allergen‐induced airway inflammation. Repealed daily exposures of actively immunised C57BL/6 mice to aerosolized ovalbumin (OVA) induced a peribronchial inflammation and an increase in eosinophils and lymphocytes in bronchoalveolar‐lavage(BAL) fluid. In IL‐4 deficient (IL4−/−) mice, treated in the same way, there were substantially fewer eosinophils in BAL and much less peribronchial inflammation compared with wild type mice. In this model, mast cell deficient (W/Wv) mice developed a similar degree of BAL eosinophilia and peribronchial inflammation as wild type mice, demonstrating that the mast cell is not required for the induction of chronic airway inflammation. In contrast, BAL eosinophilia and airway inflammation were absent in OVA‐treated MHC ClassII deficient (B6.Aa−/−) mice which lack mature CD4+ T lymphocytes. In conclusion, these results indicate that IL‐4 is a central mediator of allergic airway inflammation, regulating antigen‐induced eosinophil recruitment into the airways by a T cell dependent mechanism.

New insights into the immunology of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation.

Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials

BACKGROUND Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. METHODS We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patients body weight and randomly assigned treatment group. Additionally, the sponsors clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). FINDINGS Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37-0·67]; study 2: 0·41 [0·28-0·59]; both p<0·0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study. INTERPRETATION These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. FUNDING Teva Branded Pharmaceutical Products R&D.

Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema

Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Several mechanisms are involved in the development of the disease: influx of inflammatory cells into the lung (leading to chronic inflammation of the airways), imbalance between proteolytic and anti-proteolytic activity (resulting in the destruction of healthy lung tissue) and oxidative stress. Recently, an increasing number of data suggest a fourth important mechanism involved in the development of COPD: apoptosis of structural cells in the lung might possibly be an important upstream event in the pathogenesis of COPD. There is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema. Data from animal models suggest a role for Vascular Endothelial Growth Factor (VEGF) in the induction of apoptosis of structural cells in the lung. Other mediators of apoptosis, such as caspase-3 and ceramide, could be interesting targets to prevent apoptosis and the development of emphysema.In this review, recent data on the role of apoptosis in COPD from both animal models as well as from studies on human subjects will be discussed. The aim is to provide an up to date summary on the increasing knowledge on the role of apoptosis in COPD and pulmonary emphysema.

Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.

BACKGROUND Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a T(H)2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. OBJECTIVE The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. METHODS A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. RESULTS There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (-2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. CONCLUSION Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.

Time course of cigarette smoke-induced pulmonary inflammation in mice

Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease. In the present study a murine model of tobacco smoke-induced emphysema was used to investigate the time course of airway and pulmonary inflammatory response, with a special emphasis on pulmonary dendritic cell (DC) populations. Groups of mice were exposed to either cigarette smoke or to control air for up to 24 weeks. In response to cigarette smoke, inflammatory cells (i.e. neutrophils, macrophages and lymphocytes) progressively accumulated both in the airways and lung parenchyma of mice. Furthermore, a clear infiltration of DCs was observed in airways (10-fold increase) and lung parenchyma (1.5-fold increase) of cigarette-exposed mice at 24 weeks. Flow cytometric analysis of bronchoalveolar lavage (BAL) DCs of smoke-exposed mice showed upregulation of major histocompatability complex II molecules and costimulatory molecules CD40 and CD86, compared with BAL DCs of air-exposed mice. Morphometric analysis of lung histology demonstrated a significant increase in mean linear intercept and alveolar wall destruction after 24 weeks of smoke exposure. In conclusion, the time course of the changes in inflammatory and dendritic cells in both bronchoalveolar lavage and the pulmonary compartment of cigarette smoke-exposed mice was carefully characterised.

Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial

Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. ClinicalTrials.gov number NCT00760838.

Properties of the COPD assessment test in a cross-sectional European study

A short, easy-to-use health status questionnaire is needed in the multidimensional assessment of chronic obstructive pulmonary disease (COPD) in routine practice. The performance of the eight-item COPD assessment test (CAT) was analysed in 1,817 patients from primary care in seven European countries. The CAT has a scoring range of 0–40 (high score representing poor health status). Mean CAT scores indicated significant health status impairment that was related to severity of airway obstruction, but within each Global Initiative for Obstructive Lung Disease stage (I to IV) there was a wide range of scores (I: 16.2±8.8; II: 16.3±7.9; III: 19.3±8.2; and IV: 22.3±8.7; I versus II, p = 0.88; II versus III, p<0.0001; III versus IV, p = 0.0001). CAT scores showed relatively little variability across countries (within ±12% of the mean across all countries). Scores were significantly better in patients who were stable (17.2±8.3) versus those suffering an exacerbation (21.3±8.4) (p<0.0001); and in patients with no (17.3±8.1) or one or two (16.6±8.2) versus three or more (19.7±8.5) comorbidities (p<0.0001 for both). The CAT distinguished between classes of other impairment measures and was strongly correlated with the St George’s Respiratory Questionnaire (r = 0.8, p<0.0001). The CAT is a simple and easy-to-use questionnaire that distinguishes between patients of different degrees of COPD severity and appears to behave the same way across countries.