Articles
Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study

https://doi.org/10.1016/S2213-2600(15)00367-7Get rights and content

Summary

Background

Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood eosinophil count and prospective annual asthma outcomes for a large UK cohort.

Methods

This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12–80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541.

Findings

Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio [RR] 1·42, 95% CI 1·36–1·47) and acute respiratory events (RR 1·28, 1·24–1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72–0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less.

Interpretation

Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count–response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment.

Funding

Teva Pharmaceuticals.

Introduction

Asthma is a complex and heterogeneous disorder.1, 2 The presence of eosinophils in asthmatic inflammation has been recognised for many years, and eosinophilic asthma is a common phenotype that is usually responsive to corticosteroid therapy.3 Eosinophilic airway inflammation, as shown by raised sputum eosinophil concentrations, appears to be closely related to the risk of severe asthma exacerbations and loss of asthma control with inhaled corticosteroid withdrawal, although the pathogenetic mechanisms remain undefined.4, 5, 6 The tailoring of asthma therapy based on maintaining sputum eosinophils at 2–3% or less is effective in decreasing asthma exacerbations in patients with severe disease,4, 7 and asthma therapies targeting eosinophils are effective in reducing the incidence of asthma exacerbations and improving markers of asthma control for patients with severe eosinophilic asthma,8, 9, 10 and for patients with moderate-to-severe asthma and eosinophilia.11

Sputum eosinophil percentages of 2% or more to 3% or more of the total cells, depending on the study, have been used to define eosinophilic asthma.2, 4, 11 However, sputum induction is impractical in non-specialised clinical settings. Instead, peripheral blood eosinophil counts are easily obtained, and their use as a biomarker for increased disease burden or exacerbation risk is a topic of ongoing study. An inverse correlation between blood eosinophil counts and forced expiratory volume in 1 s (FEV1) was recorded in an earlier small study.12 In a randomised controlled trial of patients with severe eosinophilic asthma, a progressive increase in risk of exacerbation was found with increasing baseline blood eosinophils,9 and in another study of severe eosinophilic asthma, blood eosinophil counts were independently associated with both risk of exacerbation and treatment response to anti-interleukin-5 therapy, whereas sputum eosinophils did not predict response.13

Possible associations between blood eosinophil counts and overall disease burden in asthma need further study in the general population of patients with asthma, outside of clinical trials for severe asthma. Whereas a recent validation study reported that blood eosinophil counts were an accurate biomarker for identifying sputum eosinophilia,14 other studies report a lack of concordance between presence of sputum eosinophilia and blood eosinophilia.15, 16 Therefore, rather than identifying sputum eosinophils, it is probably more important to determine whether blood eosinophil counts can be used to monitor asthma control or exacerbation risk in clinical practice. In recent observational studies in the USA, raised blood eosinophil counts have been associated with increased prospective risk of asthma exacerbations and excessive short-acting reliever use,17 as well as increased historical risk of exacerbations.18, 19 A need exists to replicate these findings in other settings and databases, to study larger numbers of patients, and to examine patient-reported outcomes.

Research in context

Evidence before this study

We searched PubMed for papers published from Jan 1, 2000, to June 15, 2015, investigating the relation between blood eosinophil count and asthma outcomes, including asthma control and exacerbations, for adult patients with asthma in the general population. We used various combinations of the search terms “asthma”, “eosinophils/eosinophilia”, “exacerbation rate/risk”, and “asthma control”, and restricted our search to publications in English. We reviewed the PubMed search results and reference lists of relevant papers to identify observational studies not restricted to patients with severe or uncontrolled asthma. We identified four observational studies reporting the association between raised blood eosinophil count and increased historical or prospective risk of asthma exacerbations in general populations of patients with asthma.

Added value of this study

Our results support and extend the findings of three of these previous studies to a 40 times or greater general population of over 130 000 patients with asthma in the UK. The large cohort size enabled assessment of the prevalence of raised blood eosinophils among patients with asthma, and availability of questionnaire data for 10% of patients enabled us to look at risk in relation to Global Initiative for Asthma (GINA) current clinical control. We found that patients with raised eosinophil counts had more severe exacerbations and had poorer asthma control (more disease burden) over a subsequent year than those with a blood eosinophil count of 400 cells per μL or less; we detected a clear and consistent count–response relation between blood eosinophil count and our database-derived measures during the outcome year. Our subanalysis finding that eosinophilia was associated with an increased risk of exacerbations within GINA partly controlled and uncontrolled categories provides independent information on risk and agrees with earlier clinical trial findings of a dissociation between symptoms and risk of exacerbations for patients with severe asthma.

Implications of all the available evidence

Our findings, together with those of previous studies, suggest that patients seen in primary care with asthma and blood eosinophilia are potentially at increased risk of future exacerbations regardless of current GINA control status and should be counselled and monitored accordingly. The question remains whether the raised blood eosinophil phenotype is stable, and further research is needed to examine blood eosinophil counts in relation to timing of oral corticosteroid bursts, therapy with oral corticosteroids, and therapy or adherence with inhaled corticosteroids, again in the wider general population of patients with asthma.

Anonymised data from high-quality electronic primary care records of several million patients are available in the UK, permitting the study of very large, heterogeneous populations of patients with asthma. The primary objective of this historical primary care cohort study was to investigate the relation between blood eosinophil count and severe asthma exacerbations and asthma control during the subsequent year. A subanalysis was done to examine the relation between severe exacerbations and Global Initiative for Asthma (GINA)-defined current clinical control. Secondary objectives were to identify a potential relation between demographic and clinical characteristics and the prospective risk of raised eosinophil counts.

Section snippets

Data sources

These analyses examined data from Aug 21, 1990, to Feb 14, 2013, drawn from both the Optimum Patient Care Research Database (OPCRD)20 and the Clinical Practice Research Datalink (CPRD)21 (appendix). Patient data were cross-referenced to avoid duplication of individuals studied.

Patients and study design

Patients aged 12–80 years with an asthma diagnostic Read code, a recorded blood eosinophil count, and 1 year of continuous records both before and after their most recent blood eosinophil count (defined as the index date)

Results

We identified 343 927 patients with asthma and no other chronic respiratory disease diagnosis (figure 1). 248 858 patients met study eligibility criteria, of whom 130 248 (52%) had a recorded blood eosinophil count. Patients with available blood eosinophil counts were older and more likely to be female than those without count data (median age 49 [36–63] vs 34 [20–37] years, 88 181 [68%] vs 52 868 [45%] females, respectively; appendix), and they had greater asthma burden at baseline (24 965

Discussion

Of more than 130 000 patients with asthma and no other chronic respiratory disease diagnosis who had a recorded blood eosinophil count in their routine care medical record, we found that 20 929 (16%) had a raised peripheral blood eosinophil count of greater than 400 cells per μL. The incidence rate of severe asthma exacerbations was 42% higher, and that of acute respiratory events 28% higher, for these patients as compared with the 400 cells per μL or less eosinophil cohort, whereas the odds of

References (33)

  • A Jatakanon et al.

    Changes in sputum eosinophils predict loss of asthma control

    Am J Respir Crit Care Med

    (2000)
  • HL Petsky et al.

    A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils)

    Thorax

    (2012)
  • P Haldar et al.

    Mepolizumab and exacerbations of refractory eosinophilic asthma

    N Engl J Med

    (2009)
  • HG Ortega et al.

    Mepolizumab treatment in patients with severe eosinophilic asthma

    N Engl J Med

    (2014)
  • S Wenzel et al.

    Dupilumab in persistent asthma with elevated eosinophil levels

    N Engl J Med

    (2013)
  • CS Ulrik

    Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma

    Clin Exp Allergy

    (1995)
  • Cited by (431)

    • Refashioning dexpramipexole: A new horizon in eosinophilic asthma?

      2023, Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus
    View full text