Melanie Kjarsgaard

Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia

BACKGROUND Eosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation. METHODS In this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo. RESULTS There were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events. CONCLUSIONS Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)

Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia

BACKGROUND In patients with severe eosinophilic asthma, local maturation rather than systemic recruitment of mature cells might contribute to persistent airway eosinophilia. Group 2 innate lymphoid cells (ILC2s) are a major source of type 2 cytokines (IL-5 and IL-13) and can facilitate eosinophilic inflammatory responses in mouse models of asthma in the absence of CD4+ lymphocytes. This study investigated the potential role of ILC2s in driving chronic airway eosinophilia in patients with severe asthma, despite regular high-dose oral corticosteroid therapy. METHODS In a cross-sectional study we enumerated blood and sputum ILC2s (lin(-)CD45(+)127(+)ST2(+)) and levels of intracellular IL-5 and IL-13 in patients with severe asthma (n = 25), patients with steroid-naive mild atopic asthma (n = 19), and nonatopic control subjects (n = 5). Results were compared with numbers of CD4+ lymphocytes, eosinophil lineage-committed progenitors (eosinophilopoietic progenitor cells [EoPs]), and mature eosinophils. RESULTS Significantly greater numbers of total and type 2 cytokine-producing ILC2s were detected in blood and sputum of patients with severe asthma compared to mild asthmatics. In contrast, intracellular cytokine expression by CD4 cells and EoPs within the airways did not differ between the asthmatic groups. In patients with severe asthma, although sputum CD4+ cells were more abundant than ILC2s and EoPs, proportionally, ILC2s were the predominant source of type 2 cytokines. In addition, there were significantly greater numbers of sputum IL-5(+)IL-13(+) ILC2s in patients with severe asthma whose airway eosinophilia was greater than 3%, despite normal blood eosinophil numbers (<300/μL). CONCLUSIONS Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.

Heterogeneity of Bronchitis in Airway Diseases in Tertiary Care Clinical Practice

BACKGROUND Sputum cell counts have identified inflammatory subtypes of bronchitis in relatively small numbers of subjects with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough in research studies. The prevalence of different subtypes of bronchitis in routine clinical practice, however, has not been reported. OBJECTIVE To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction. METHODS A retrospective cross-sectional survey based on a computerized database of spontaneous or induced sputum cell counts examined in a large university tertiary respiratory outpatient clinic. RESULTS The database contained 4232 consecutive sputum records from 2443 patients with chronic cough (39%), asthma (37%), asthma with COPD (9%), COPD (13%) and bronchiectasis (3%). Total and differential cell counts were obtained from 86% of successful sputum samples. Induced sputum provided more viable samples than spontaneous expectorate. Approximately one-third of patients with asthma and one-fifth of patients with COPD experience eosinophilic bronchitis. Asthmatic patients with moderate to severe airflow obstruction had a greater number of sputum eosinophils. There was a significantly higher number of total cell counts and percentage of neutrophils in the sputum of COPD patients with moderate and severe airflow obstruction than in those with mild airflow obstruction. CONCLUSION There is heterogeneity in the cellularity of sputum in various airway diseases. Patients with clinically stable airway diseases may have high sputum cell counts. During exacerbations, more patients may experience neutrophilic bronchitis. Severity of airflow obstruction is associated with eosinophilic bronchitis in patients with asthma, and neutrophilic bronchitis in patients with nonasthmatic COPD.

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

In severe asthmatics with persistent airway eosinophilia, blockade of interleukin‐5 has significant steroid‐sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics.

Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab

Rationale: Clinical benefits of fixed‐dose 100‐mg subcutaneous (SC) mepolizumab in prednisone‐dependent patients are modest when sputum eosinophilia is not adequately controlled. Objectives: This study compared treatment response of weight‐adjusted intravenous (IV) reslizumab in patients previously treated with 100‐mg SC mepolizumab. Methods: Ten prednisone‐dependent patients with asthma (sputum eosinophils >3% and blood eosinophils >300 cells/&mgr;l), who had previously received mepolizumab (100 mg SC dosed every 4 wk [Q4W]) for at least 1 year, received two infusions of placebo (Q4W) followed by four infusions of 3.0 mg/kg reslizumab Q4W in a single‐blind, placebo‐controlled sequential trial. Primary outcomes were reduction of eosinophils in sputum and blood. Additional outcomes included FEV1, asthma control questionnaire, eosinophil peroxidase, IL‐5, sputum and blood innate lymphoid cells group 2, eosinophil progenitor cells, and autoimmune responses. Measurements and Main Results: IV reslizumab attenuated sputum eosinophils by 91.2% (P = 0.002), blood eosinophil counts by 87.4% (P = 0.004), and sputum eosinophil peroxidase levels by 65.5% (P = 0.03) compared with placebo. Attenuation of both local and systemic eosinophilia was associated with statistically significant improvements in FEV1 (P = 0.004) and asthma control questionnaire five‐question instrument scores (P = 0.006). Decrease in percent sputum eosinophil was greater with reslizumab (by 42.7%) compared with mepolizumab (by 5.0%) and this was associated with greater improvement in asthma control questionnaire (P = 0.01; analysis of covariance of &Dgr; between before and after treatment, mepolizumab vs. reslizumab, adjusted for baseline prednisone). Changes in sputum IL‐5 and anti‐eosinophil peroxidase IgG after anti‐IL‐5 therapy were predictors of response. Conclusions: Weight‐adjusted IV reslizumab was superior to fixed‐dose SC mepolizumab in attenuating airway eosinophilia in prednisone‐dependent patients with asthma, with associated improvement in asthma control. Clinical trial registered with www.clinicaltrials.gov (NCT 02559791).

A pilot randomised clinical trial of mepolizumab in COPD with eosinophilic bronchitis.

Airflow limitation in chronic obstructive pulmonary disease (COPD) is associated with influx of various inflammatory cells (e.g. eosinophils, neutrophils, lymphocytes, macrophages) into the airways. Approximately one-third of stable COPD patients and one in five COPD exacerbations are associated with eosinophilic bronchitis that usually responds to inhaled or ingested corticosteroids [1]. Specific anti-eosinophil agents like mepolizumab, a humanised monoclonal antibody against interleukin 5 (IL-5), reduce severe asthma exacerbations and improve lung function [2–4]. The improvement in forced expiratory volume in 1 s (FEV1) is also associated with a decrease in biomarkers of airway remodelling, such as sputum hyaluronan and versican, over a 6-month treatment period [5]. It is not known if the same benefits are observed in patients with COPD and eosinophilia in whom the airflow obstruction is due to cigarette smoke-related bronchitis and emphysema. Eosinophils may not directly contribute to luminal obstruction in COPD although they may predict steroid response http://ow.ly/b3Au308wA0m

Cytokine responses of peripheral blood mononuclear cells to allergen do not identify asthma or asthma phenotypes

Asthmatic patients are often differentiated based on their atopic status (atopic or nonatopic) and type of bronchitis (eosinophilic, neutrophilic, both, or neither). There is evidence supporting a central role for the T cell in asthma, but the role of allergen‐induced T cell cytokines in driving disease in different asthma phenotypes remains unclear.

A Multidimensional Approach to the Management of Severe Asthma: Inflammometry, Molecular Microbiology and Bronchial Thermoplasty

The authors illustrate the merits of identifying the components of diseases (eg, bronchitis and airway hyper-responsiveness) that contribute to exacerbations in the management of a patient with severe asthma. Quantitative cell counts in sputum identified a neutrophilic – as opposed to eosinophilic – bronchitis that enabled a stepwise weaning of prednisone. Molecular microbiology and extended culture methods identified anaerobes and other airway microbiome that helped to guide the use of antibiotics. Further control of asthma was achieved by performing bronchial thermoplasty.

Dysregulation of Vascular Endothelial Progenitor Cells Lung-Homing in Subjects with COPD

Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow limitation and progressive decline of lung function and punctuated by occasional exacerbations. The disease pathogenesis may involve activation of the bone marrow stimulating mobilization and lung-homing of progenitor cells. We investigated the hypothesis that lower circulating numbers of vascular endothelial progenitor cells (VEPCs) are a consequence of increased lung-sequestration in COPD. Nonatopic, current or ex-smokers with diagnosed COPD and nonatopic, nonsmoking normal controls were enrolled. Blood and induced sputum extracted primitive hemopoietic progenitors (HPCs) and VEPC were enumerated by flow cytometry. Migration and adhesive responses to fibronectin were assessed. In sputum, VEPC numbers were significantly greater in COPD compared to normal controls. In blood, VEPCs were significantly lower in COPD versus normal controls. There were no differences in HPC levels between the two groups in either compartment. Functionally, there was a greater migrational responsiveness of progenitors from COPD subjects to stromal cell-derived factor-1alpha (SDF-1α) compared to normal controls. This was associated with greater numbers of CXCR4+ progenitors in sputum from COPD. Increased migrational responsiveness of progenitor cells may promote lung-homing of VEPC in COPD which may disrupt maintenance and repair of the airways and contribute to COPD disease pathogenesis.

Sputum autoantibodies in patients with severe eosinophilic asthma

Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti‐nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high‐dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. Results: We report a “polyclonal” autoimmune event occurring in the airways of prednisone‐dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti‐EPX and anti‐nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2‐dominated microenvironment (eotaxin‐2, IL‐5, IL‐18, and IL‐13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B‐cell activating factor and B cell–attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone‐rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid‐unresponsive nature of these eosinophilic patients. Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.