Debbie Parker

Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.

BACKGROUND Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy. METHODS We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat. FINDINGS The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups. INTERPRETATION A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids

Background: The debate as to whether asthma is a single or heterogeneous disease remains unresolved although pathological studies, mostly using fibreoptic bronchoscopy on small numbers of subjects, have emphasised the similarities between different clinical phenotypes. Methods: Lower airway inflammation was assessed non-invasively using induced sputum in 34 normal controls and 259 adults with symptomatic asthma receiving treatment at steps 1–3 of the British Thoracic Society (BTS) guidelines. A subgroup of 49 patients treated with as required β2 agonists only who met BTS criteria for a step up in treatment were studied before and 2 months after treatment with inhaled budesonide 400 μg twice daily. Results: There was considerable heterogeneity in induced sputum cell counts, particularly in non-atopic patients. A subgroup of 60 patients had a distinctive sputum cell profile with a neutrophil count higher than our normal range (>65.3%) and a normal sputum eosinophil count (<1.9%). These patients were older, predominantly female, and were more likely to be non-atopic but otherwise had similar clinical and physiological features to the group as a whole. Among the 49 subjects studied before and after inhaled budesonide, 11 patients had an isolated sputum neutrophilia. Following treatment, these patients showed significantly less improvement in visual analogue symptom scores (–5.5 v –19.4 mm; mean difference 13.9; 95% CI 0.7 to 27.0), forced expiratory volume in 1 second (FEV1) (–0.08 v 0.13 l; mean difference 0.21; 95% CI 0.03 to 0.39), and concentration of methacholine provoking a fall in FEV1 of 20% or more (PC20) (0.15 v 1.29 doubling doses; mean difference 1.11; 95% CI 0.13 to 2.15) than the remaining 38 patients. Conclusions: These results suggest the presence of a distinct subgroup of patients with mild to moderate asthma who have predominantly neutrophilic airway inflammation and who respond less well to treatment with inhaled corticosteroids.

Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial

BACKGROUND Some patients with chronic obstructive pulmonary disease (COPD) respond to corticosteroid therapy. Whether these patients have different airway pathology from other COPD patients is unclear. We tested the hypothesis that response to prednisolone is related to the presence of eosinophilic airway inflammation. METHODS We did a randomised, double-blind, crossover trial. Patients who had COPD treated with bronchodilators only were assigned placebo and 30 mg prednisolone daily for 2 weeks each, in a random order, separated by a 4-week washout period. Before and after each treatment period, we assessed patients with spirometry, symptom scores, the chronic respiratory disease questionnaire (CRQ), incremental shuttle walk test, and induced sputum. Analysis was done by intention to treat. FINDINGS 83 patients were recruited, of whom 67 were randomised. The geometric mean sputum eosinophil count fell significantly after prednisolone (from 2.4% to 0.4%; mean difference six-fold [95% CI 3.1-11.4]) but not after placebo. Other sputum cell counts did not change. After stratification into tertiles by baseline eosinophil count, postbronchodilator forced expiratory volume in 1 s (FEV1) and total scores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophilic tertile, compared with placebo. The mean change in postbronchodilator FEV1, total CRQ score, and shuttle walk distance with prednisolone compared with placebo in the highest tertile was 0.19 L (0.06-0.32), 0.62 (0.31-0.93), and 20 m (5-35), respectively. INTERPRETATION Our findings suggest that eosinophilic airway inflammation contributes to airflow obstruction and symptoms in some patients with COPD and that the short-term effects of prednisolone are due to modification of this feature of the inflammatory response. The possibility that sputum eosinophilia identifies a subgroup of patients who particularly respond to long-term treatment with inhaled corticosteroids should be investigated.

Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease

Background: An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear. Methods: A randomised, double blind, crossover trial of placebo and mometasone furoate (800 μg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase. Results: Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV1), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV1 increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV1 with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count. Conclusions: An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV1 following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma

Background CRTH2 is a G‐protein‐coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D2 and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma.

The influence of age on induced sputum differential cell counts in normal subjects.

STUDY OBJECTIVES Sputum induction is increasingly used as a research technique and as a clinical tool. In order to evaluate abnormal results, normal ranges need to be fully developed. Although a number of studies have described normal ranges, none have investigated the effect of the age of the subject on these results. This study was undertaken to assess whether there are age-related differences in sputum cell differential cell counts in a population of normal, healthy volunteers. STUDY DESIGN AND PARTICIPANTS Induced sputum samples were obtained from 66 healthy, nonsmoking subjects (24 men) with a mean age of 44 years (age range, 18 to 74 years). Differential cell counts were related to age. RESULTS Sputum neutrophil counts were found to correlate significantly with the age of the volunteers (r = 0.58; p < 0.001). Macrophage counts showed a proportionate, inverse correlation with increasing age (p < 0.01), but no correlation was seen for any other cell type. On subanalysis according to age range, the mean neutrophil differential increased from 26.9% (SD, 19.8%) [17 patients] in the group of patients who were 0 to 29 years of age to 68.5% (SD, 20.6%) [11 patients] in the group of patients who were > 60 years of age. CONCLUSION In our healthy volunteer population, the induced sputum differential neutrophil count increased significantly with age. These findings highlight the need for age matching in controlled studies.

Profiling of Sputum Inflammatory Mediators in Asthma and Chronic Obstructive Pulmonary Disease

Background: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown. Objectives: To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD. Methods: Subjects with asthma and COPD (n = 54 and n = 49) were studied. Clinical characteristics and sputum were collected at entry into the study. A 2-step sputum processing method was performed for supernatant and cytospin preparation. Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. Results: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1β, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3–5.4), p = 0.01; TNFRI, 2.1 (1.3–5.4), p = 0.03; TNFRII, 2.6 (1.2–5.6), p = 0.02]. In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. Conclusion: Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated.

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 μg b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 μg b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5–0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7–1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2–2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Granulocyte–macrophage colony-stimulating factor expression in induced sputum and bronchial mucosa in asthma and COPD

Background: Granulocyte–macrophage colony-stimulating factor (GM-CSF) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of GM-CSF and its receptor in airway samples in asthma and COPD across disease severity needs to be further defined. Methods: Sputum GM-CSF was measured in 18 control subjects, 45 subjects with asthma and 47 subjects with COPD. Enumeration of GM-CSF+ cells in the bronchial submucosa and airway smooth muscle bundle was performed in 29 control subjects, 36 subjects with asthma and 10 subjects with COPD. Results: The proportion of subjects with measurable GM-CSF in the sputum was raised in those with moderate (7/14) and severe (11/18) asthma, and in those with COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II (7/16), III (8/17) and IV (7/14) compared with controls (1/18) and those with mild asthma (0/13); p = 0.001. The sputum GM-CSF concentration was correlated with the sputum eosinophilia in subjects with moderate to severe asthma (rs = 0.41; p = 0.018). The median (interquartile range) GM-CSF+ and GM-CSFR+ cells/mm2 of submucosa was increased in severe asthma (1.4 (3.0) and 2.1 (8.4)) compared with those with mild to moderate asthma (0 (2.5) and 1.1 (5)) and healthy controls (0 (0.5) and 0 (1.6)), (p = 0.004 and p = 0.02, respectively). Conclusions: The findings support a potential role for GM-CSF in asthma and COPD and suggest that overexpression of GM-CSF in sputum and the bronchial mucosa is a particular feature of severe asthma.