Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis

Inhaled corticosteroid (ICS) therapy has been reported to be associated with a reduction in the risk of moderate and severe exacerbations in a subgroup of patients with chronic obstructive pulmonary disease (COPD) [1]. Those COPD patients with predominantly eosinophilic airways inflammation [2] may derive the most benefit from ICS use [3‐7]. International guidelines reflect this targeted approach to ICS prescription [8]. The peripheral blood eosinophil count, absolute and relative, has high correlation with sputum eosinophils [9] and has gained increased recognition as a proxy of eosinophilic airways inflammation [10]. In one stable state COPD population 37.4% of patients had a blood eosinophil count of ≥2% [11]. This threshold may predict response to ICS treatment with respect to modification of exacerbation risk in COPD patients [12]. Evidence for this association has been derived from post-hoc analyses of randomised controlled trials (RCTs) [10]. High rates of prescription of ICS, outside guidelines, highlight the importance of targeted prescribing for patients with COPD. In primary care in England, 24% of COPD patients were prescribed ICS and long-acting beta-agonists (LABA) outside of the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [13]. Between 2007 and 2010, large increases in ICS prescribing were not associated with expected impact on the incidence of admissions for exacerbations [14, 15].

The stability of the blood eosinophil count has been questioned, raising doubts about the appropriateness of using a single measurement as a reliable predictor of ICS response [16]. A cohort study of COPD patients with moderate airflow limitation did not find a relationship between numbers of tissue eosinophils in the airways and lung parenchyma and blood eosinophils [17]. Studies examining the role of blood eosinophils as a biomarker of ICS sensitivity have selected different thresholds of relative and absolute counts in their analyses. Previous reviews, in their comparisons of the impact on exacerbation risk of ICS vs. non-ICS, have not isolated the effect of the ICS from that of bronchodilators [7, 12]. A recent systematic review examined the impact of triple therapy vs. dual bronchodilator therapy among patients with blood eosinophilia but did not stratify the studies by eosinophil threshold [6]. An assessment of blood eosinophil count as a marker of the independent effect of ICS on reduction of exacerbation frequency would help to clarify the value of this biomarker as a guide to the prescription of these drugs.

We have chosen three thresholds as likely markers of corticosteroid-responsive disease. An association has been found between blood eosinophil counts of ≥2% and an increased risk of severe exacerbations and mortality from exacerbations among patients with COPD [18]. The benefits of oral corticosteroids have been found only in those patients with blood eosinophils of ≥2% [19]. A correlation has been reported between a relative blood eosinophil count of 2% and an absolute blood eosinophil count of 150 cells/μL [20]. The GOLD guidelines recommend the use of an absolute blood eosinophil count of ≥300 cells/μL to identify patients with COPD who should escalate their treatment from use of long-acting beta-agonist + long-acting muscarinic antagonist (LABA+LAMA) to use of LABA+ICS [8]. This systematic review provides an up-to-date analysis of the predictive value of three blood eosinophil thresholds (2%, 150 cells/μL, and 300 cells/μL) as biomarkers of the independent impact of ICS use on the risk of moderate and severe exacerbations in COPD patients. These findings are compared to those of real-world observational studies.

The population of this review were patients with COPD stratified by blood eosinophil count. Blood eosinophil thresholds of 2%, 150 cells/μL, and 300 cells/μL were examined. The intervention was the use of inhaled corticosteroids at any dosage. The comparison was the use of ICS with any non-ICS combination inhaler or placebo (all association studies). A separate analysis examined the independent effect of ICS by comparing use of ICS monotherapy vs. placebo, or ICS + LABA vs. LABA, or ICS + LABA+LAMA vs. LABA+LAMA (ICS-independent association studies). The outcome was the risk of moderate or severe exacerbations of COPD. The report follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement (PRISMA) guidelines [21].

Five thousand five hundred eighty-three studies were identified and screened (Fig. 1 PRISMA flow chart). The full texts of 451 studies were assessed for eligibility. 16 studies fulfilled the inclusion criteria. Eleven of these studies [20, 25‐34], comprising 25,881 patients, were post-hoc analyses of data from 13 RCTs (Table 1). The remaining 5 studies [35‐39], comprising 109,704 patients, were retrospective observational studies (Table 2). Relevant data published from two post-hoc analyses of four RCTs were not presented in a form that could be incorporated in this review [5, 40]. The data were sought from the companies holding the data but had not been received in time for inclusion in this review. Search strategies are included see Additional file 1: Tables S3, S4, S5, S6, S7 and S8.

The post-hoc analyses of RCTs were divided into those which had balanced treatment arms except for ICS, and those where one arm received an additional treatment (typically a LAMA). The independent effect of the ICS on risk of moderate or severe exacerbation was isolated in the RCTs which had balanced treatment arms [20, 25‐28, 31‐34] but not in those which did not [26, 29, 30]. One study [26] reported the results of three different RCTs: INSPIRE, TRISTAN and SCO30002. The INSPIRE study did not isolate the independent effect of the ICS whereas the TRISTAN and SCO30002 studies did. The TRISTAN study comprised five different drug comparisons. Two of these, Fluticasone propionate (FP) + Salmeterol (SAL) vs. SAL and FP vs. placebo, isolated the independent effect of the ICS. The patient groups in these two drug comparisons were mutually exclusive. These have been labelled here as TRISTAN I (FP/SAL vs. SAL) and TRISTAN II (FP vs. placebo) and treated as two separate investigations in the meta-analysis.

Our meta-analysis has identified a positive association between use of ICS and risk of moderate or severe COPD exacerbations when stratified by blood eosinophil threshold. When all studies were examined the positive association was present at ≥2% and ≥ 150 cells/μL eosinophil thresholds, but not at the ≥300 cells/μL threshold. When the independent effect of ICS was isolated the association was positive at each of the three thresholds and the degree of the association/effect size had increased. The evidence for the association at each of these thresholds was low or very low.

A lack of association between use of ICS and risk of moderate or severe COPD exacerbations was found in 4 of the 5 observational studies [35, 37‐39]. Reasons for the difference in results between the two types of studies may include differences in patient demographics, or differences between bronchodilator use by participants of the RCTs compared to those of the observational studies. The results of the observational studies may be less reliable than those of the RCTs due to differences in quality between the two types of studies. It has been estimated that those patients with COPD selected for clinical trials are representative of about 7% of the entire COPD population [41].

Eleven of the 13 RCTs recruited only patients with a history of ≥1 exacerbation in the past 12 months. In three of the observational studies [35, 36, 39] the proportion of patients reported to have experienced ≥1 exacerbation in the past 12 months was between 32 & 41%. The remaining two observational studies excluded patients who had experienced an exacerbation either in the 6 months prior to the index date [38] or at any point in the past [37]. COPD patients with the greatest degree of airflow impairment may experience the largest number of exacerbations. All of the RCTs recruited patients with either severe to very severe airflow limitation [27, 32] or moderate to severe airflow limitation. In 3 of the 5 observational studies the disease severity of the patients was unknown [36‐38]. Participants in the remaining 2 observational studies had a mean FEV1% predicted of > 50% [35, 39]. The severity of airflow limitation of patients in the RCTs is likely to have been greater and their baseline exacerbation prevalence higher than those in the observational studies. The effect of ICS use is likely to be more apparent within the RCTs in comparison to the observational studies.

One potential explanation of the disparity in results could be a higher rate of undiagnosed asthma among the participants of the RCTs compared with the observational studies. Patients with a current diagnosis of asthma were excluded in all but one of the RCTs [20, 26‐34]. Three RCTs recruited patients who may have had a past diagnosis of asthma [20, 28, 34]. Eleven RCTs undertook reversibility testing [20, 25, 26, 29‐34] and 4 of these RCTs excluded patients with a reversibility of > 10% [25, 26]. The remaining 7 RCTs [20, 29‐34] included patients with reversibility, an indicator of asthma, their prevalence ranging from 10 to 25%. In 4 of 5 observational studies participants with an asthma diagnosis were excluded [35, 37‐39]. The one observational study that did not exclude patients with asthma found a positive association at blood eosinophil thresholds ≥4% and ≥ 300 cells/μL between use of LABA+ICS and a decrease in exacerbation frequency, compared to use of LAMA [36]. It is probable that both the RCTs and observational studies included a proportion of patients with asthma/reversibility, in whom the association between ICS use and reduction in exacerbation risk would be strongest. A baseline blood eosinophil count of ≥500 cells/μL has been identified in 30% of patients with asthma [42] but in only 3.3% of patients with COPD [17]. The FLAME study, one of the few RCTs which failed to find an association between eosinophil count and impact of ICS in COPD patients, excluded those patients with blood eosinophils ≥600 cells/μL [30].

Use of concurrent bronchodilators among patients in the observational studies, but not those of the RCTs, may have contributed to the lack of association found between ICS use and risk of exacerbations in the observational studies. The findings of the observational studies raise questions about the transferability of the post-hoc RCT findings to real world clinical practice. A strong association between impact of ICS and risk of exacerbations at the three eosinophil thresholds was evident from the meta-analysis. Any new prospective trial with randomization by eosinophil status is unlikely to come up with an assessment of efficacy of ICS in preventing exacerbations in COPD in patients above the experimental threshold that gives a different result. However, the observational studies do suggest that the effectiveness of ICS using the eosinophil threshold of 2% (or 150 cells/μL) in a real-world setting cannot be assumed from efficacy trials. An effectiveness trial, which excludes patients with asthma, may help in answering this question. A limitation of the observational studies is the lack of consistency in the reporting of concurrent bronchodilator use among participants. However, it is exactly these factors together with differences in clinical and demographic characteristics that make effectiveness trials so important in testing the applicability of efficacy trials which have such tight inclusion and exclusion criteria as drug trials in COPD.

This review has examined the predictive value of blood eosinophils on the impact of ICS when patients are stratified by both relative and absolute blood eosinophil counts. The relative blood eosinophil count will be altered by the numbers of other cells within the white blood cell population. This suggests that the relative blood eosinophil count is inherently less reliable than the absolute blood eosinophil count. Despite this we have identified a positive association at raised thresholds of both the relative and absolute blood eosinophil counts.

GOLD guidelines recommend escalation from dual LABA+LAMA therapy to LABA+ICS in patients with blood eosinophil counts ≥300 cells/μL or in those with blood eosinophils of ≥100 cells/μL and a history of ≥2 exacerbations or 1 severe exacerbation [8]. The meta-analysis by Oshagbemi et al. identified a positive association between ICS use and reduction in exacerbation risk at blood eosinophil thresholds of ≥100 to ≥340 cells/μL [7]. They did not stratify the results into narrower eosinophil ranges, nor did they differentiate by past exacerbation history. The effect, or lack of effect of ICS on exacerbation risk at low eosinophil thresholds may have been over-ridden by the effect seen at higher eosinophil thresholds. Their findings confirm the GOLD recommendation for use of ICS at eosinophil threshold ≥300 cells/μL but do not directly justify use at eosinophil threshold ≥100 cells/μL accompanied by a history of ≥2 exacerbations or 1 severe exacerbation. Bafadhel et al. described a continuous relationship between blood eosinophil count and the impact of budesonide on reduction in exacerbation risk [5]. At eosinophil counts of < 200 cells/μL the confidence intervals were broad and the upper limit close to one.

The blood eosinophil count may help characterize the nature of exacerbations within a population of patients with COPD who experience exacerbations. Its value is less clear for those patients with COPD who do not have exacerbations. The eosinophil count may be elevated for other reasons including allergies, inflammatory conditions and malignancies. In addition, a single blood eosinophil count may be an unsatisfactory basis upon which to prescribe ICS.

This meta-analysis has demonstrated a positive association and a strong effect size, across three blood eosinophil thresholds – 2%, 150 cells/μL and 300 cells/μL, between ICS, independently assessed, and the risk of an exacerbation of COPD. The strength of the association was less when the contributory effects of the bronchodilators were not excluded. The strength of the association increased as the blood eosinophil threshold increased. The quality of the evidence for these associations was low or very low. Data from the post-hoc RCTs may not justify extrapolation to the general COPD population. The lack of association found in the observational studies suggests that this relationship may not be present within the “real world” COPD population. A prospective effectiveness study which differentiates patients according to past exacerbation history and reversibility of lung function and stratified by ranges of eosinophil counts rather than eosinophil thresholds should be conducted.