Articles
Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort

https://doi.org/10.1016/S2213-2600(17)30432-0Get rights and content

Summary

Background

Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils.

Methods

We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344).

Findings

Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per μL) and 1237 with high (≥200 cells per μL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1·25%) and 171 with high (≥1·25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p<0·0001) and after (77·3% [63·1–88·5] vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p<0·0001), but with a high false-discovery rate of 72%.

Interpretation

In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils.

Funding

National Institutes of Health, and National Heart, Lung, and Blood Institute.

Introduction

Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by increased concentrations of neutrophils,1 macrophages,2 proteases, interleukin 6 and 8, and T-helper-1 (Th1) cytokines,3 whereas airway inflammation in asthma is characterised by increased concentrations of eosinophils and Th2 cytokines.4 However, some research has challenged these presumed differences between the characteristic markers of asthma and COPD.

Research in context

Evidence before this study

We did a PubMed search for original research reports using the search terms “eosinophils”, “sputum”, “blood”, and “COPD” from April 15, 2014, to May 18, 2017, which yielded 154 articles, of which 32 were reviews. No publication date or language restrictions were used. Addition of “severity” as a search term reduced the publication number to 33 (seven reviews) and addition of “exacerbation” reduced the number to 35 (one review). However, many of these reports have further limitations. Some did not have sputum or blood eosinophil data for comparison, did not specifically focus on the severity of chronic obstructive pulmonary disease (COPD; eg, exacerbations), or were based on small numbers of patients (<100 per group), which limits the power to make conclusions for broader COPD populations. Generally, eosinophils in COPD have been linked to more frequent exacerbations and responsiveness to corticosteroid therapy, suggesting more severe disease. Often, studies are done primarily in populations that have met selection criteria for clinical trials, including the presence of COPD exacerbations. Thus, comparison of blood and sputum eosinophil concentrations for an association with severity of COPD phenotype has not been well studied in a general smoking population with a broad range of COPD severity, nor has possible substitution of blood eosinophils as a biomarker for sputum eosinophils in COPD populations been carefully examined.

Added value of this study

This study shows that in a large, comprehensively characterised smoking cohort with a broad range of COPD severity, increased sputum eosinophils, but not blood eosinophils alone, had significant associations with multiple measures of COPD severity, including exacerbations, increased emphysema and air trapping, St George Respiratory Questionnaire scores, and Global Initiative for Chronic Obstructive Lung Disease spirometric stage. Blood eosinophils showed weak association with sputum eosinophils and as a single biomarker had few significant associations with COPD severity and exacerbations. However, this study does show that increased blood eosinophils in combination with increased sputum eosinophils show associations with COPD exacerbations and severity.

Implications of all the available evidence

Increased sputum eosinophils in patients with a broad range of COPD severities identify patients who are more likely to have severe disease and exacerbations. Blood eosinophils as a single biomarker do not accurately predict sputum eosinophils, and do not show any association with disease severity or exacerbations unless observed in combination with increased sputum eosinophils. The findings from this study will be important in the design of therapeutic trials that target eosinophilic inflammation in COPD.

The ECLIPSE study1 reported that in COPD, sputum neutrophil concentrations were weakly associated with lung function and health status, but not associated with exacerbations, emphysema, or systemic inflammation. ECLIPSE reported a mean 1·3% (SD 2·6) sputum eosinophil concentration in 359 patients with COPD,1 but did not observe associations of blood eosinophils with radiological measures of emphysema or with COPD exacerbations and hospital admissions. ECLIPSE reported that concentrations of persistently 2% or more blood eosinophils (150 cells per μL) were associated with evidence of higher FEV1, lower St George Respiratory Questionnaire (SGRQ) score, and modified Medical Research Council score compared with intermittent concentrations or concentrations persistently less than 2%.5 Other COPD studies have reported that increased eosinophils in both blood and sputum are associated with respiratory exacerbations and greater hyperinflation when assessed by quantitative CT (QCT),6, 7 suggesting that Th2 inflammation might contribute to COPD progression. Furthermore, increased epithelial Th2 signature gene expression has been associated with more severe airflow obstruction in two COPD cohorts.8 Eosinophils might therefore be a potential biomarker in COPD because eosinophilia is related to corticosteroid responsiveness.1, 9, 10, 11 In a phase 2 clinical trial, anti-interleukin-5 receptor therapy reduced the occurrence of COPD exacerbations in a subgroup of patients with high concentrations of blood and sputum eosinophils.12

Establishing disease severity in patients with COPD is complex and involves more than lung function assessments; additional clinical characteristics have been incorporated in successive revisions of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity stages.13 The current classification includes lung function, symptom scores, and exacerbation frequency. Thus, the severity of COPD is dependent on multiple characteristics, and eosinophilic inflammation might contribute.

Previous reports suggest that blood eosinophil counts might be a useful surrogate measure of airway eosinophils in COPD,11, 14 although blood eosinophils appear to correlate poorly with sputum eosinophils in asthma,15, 16 and do not distinguish between populations who are asthma dominant, COPD dominant, or those who have asthma–COPD overlap.17 However, larger studies of comprehensively phenotyped patients with COPD often do not have robust sputum eosinophil data either because sputum induction was not done or sputum induction cohorts were small.18, 19, 20, 21 Thus, whether or not peripheral eosinophils do accurately predict airway eosinophils is unknown.

We investigated the hypotheses that high concentrations of blood and sputum eosinophils in patients with a history of tobacco use are associated with a more severe COPD phenotype, identified by diminished lung function, QCT measurements of emphysema or air-trapping, clinical COPD characteristics, and exacerbations. We also investigated relationships between blood and sputum eosinophils to establish whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. Measuring blood eosinophils is an easier and less expensive option than sputum induction in a clinical setting. Thus, an ability to predict sputum eosinophils accurately from blood eosinophil concentrations would be useful for clinical studies and patient care. These hypotheses were assessed in the comprehensively characterised SPIROMICS cohort.22 A portion of these studies were presented as an abstract at the 2016 American Thoracic Society meeting.23

Section snippets

Study design and patients

We did a multicentre observational study of baseline data of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Individuals aged 40–80 years with current or former history of tobacco use (≥20 pack-years) were enrolled in SPIROMICS at six clinical sites and additional subsites in the USA.22 2737 patients were recruited to the SPIROMICS cohort between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with

Results

Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts (figure 1). Mean blood eosinophil count in these 2499 patients was 200 cells per μL (SD 240; median 190 cells per μL [IQR 100–250]; range 0–8300 cells per μL), thus, 200 cells per μL was used as the cutoff for analyses. A higher eosinophil cutoff of 300 cells per μL was also examined. The 2499 patients were grouped according to their blood eosinophil count: 1262 patients with low (<200 cells

Discussion

This study in patients from the SPIROMICS cohort, who were smokers with COPD of varying severity as defined by GOLD stages, confirms that high concentrations of sputum eosinophils, but not blood eosinophils (unless in combination with high sputum eosinophils), identify a subset of patients with COPD with more severe airflow obstruction, worse quality of life, greater emphysema and air trapping, and greater number of exacerbations. Using sputum eosinophil stratification with cutoffs at either

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