Articles
Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial

https://doi.org/10.1016/S2213-2600(20)30053-9Get rights and content

Summary

Background

Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment.

Methods

In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only β agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 μg in a pressurised metered dose inhaler), maintenance budesonide (200 μg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 μg), or as-needed budesonide–formoterol (one inhalation of 200 μg budesonide and 6μg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538.

Findings

675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with <0·15 × 109/L, six [6%] of 93 with 0·15 to <0·3 × 109/L, and 15 [19%] of 77 with ≥0·3 × 109/L; p=0·014). There were no significant interactions between blood eosinophil count or FeNO level and the effect of as-needed budesonide–formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil count subgroups and the effect of maintenance budesonide plus as-needed salbutamol compared with as-needed salbutamol, both for exacerbations (p=0·0006) and severe exacerbations (p=0·0007). Maintenance budesonide plus as-needed salbutamol was more effective than as-needed salbutamol in patients with blood eosinophil counts of 0·3 × 109/L or more, both for exacerbations (rate ratio 0·13 [95% CI 0·05–0·33]) and severe exacerbations (risk odds ratio 0·11 [0·03–0·45]). This difference was not seen for blood eosinophil counts of less than 0·15 × 109/L (1·15 [0·51–1·28] for exacerbations and 5·72 [0·97–33·60] for severe exacerbations). There was no consistent interaction between treatment response and FeNO or the composite score.

Interpretation

In patients with mild asthma, the effects of as-needed budesonide–formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts.

Funding

AstraZeneca, Health Research Council of New Zealand.

Introduction

Patients with mild or episodic asthma often struggle to commit to treatment with regular inhaled corticosteroids. This low adherence is a problem because even minimally symptomatic patients have a risk of exacerbations, and the beneficial effect of maintenance inhaled corticosteroid (ICS) therapy on exacerbation frequency is substantial.1 Identification of a biomarker associated with the risk of exacerbations and the likelihood of a response to ICS would be a considerable advance.

In patients with more severe asthma and chronic obstructive pulmonary disease (COPD), increased sputum and blood eosinophil counts are associated with increased risk of exacerbations and identify those most likely to benefit from ICS.2, 3, 4, 5, 6, 7, 8, 9, 10 Exhaled nitric oxide (FeNO), an important biomarker of type 2 airway inflammation, is also associated with risk of adverse asthma outcomes, and a composite score including FeNO and blood eosinophil counts might improve the prediction of future risk in patients with severe asthma.4, 5 Whether these biomarkers have prognostic value or predict the effect of ICS on exacerbations in mild asthma is unclear.

Research in context

Evidence before this study

In patients with more severe asthma and chronic obstructive pulmonary disease (COPD), sputum and blood eosinophil counts are associated with increased risk of exacerbations and a beneficial effect of inhaled corticosteroids (ICS). Exhaled nitric oxide (FeNO) is also associated with risk of adverse asthma outcomes, and a composite score including FeNO and blood eosinophil count might improve the prediction of future risk in response to treatment in patients with severe asthma. Whether these biomarkers have prognostic value or predict the effect of regular or as-needed ICS on exacerbations in patients with mild asthma is not certain. The identification of a prognostic and predictive biomarker in this group would be a substantial advance because although ICS are effective at a population level, many patients have a low burden of symptoms and exacerbations and struggle to commit to treatment with regular ICS.

Added value of the study

This study is a prespecified subgroup analysis of a 52-week, open-label, parallel-group randomised controlled trial in patients with mild asthma, which compared as-needed salbutamol with maintenance budesonide plus as-needed salbutamol and with as-needed budesonide–formoterol. Compared with patients with baseline blood eosinophil counts of less than 0·15 × 109/L, patients with blood eosinophil counts of 0·3 × 109/L or more had similar baseline Asthma Control Questionnaire scores and FEV1 % predicted, but they were three times as likely to have ever had an asthma exacerbation requiring hospital admission. In patients with blood eosinophil counts of 0·3 × 109/L or more, maintenance budesonide plus as-needed salbutamol was more effective than only as-needed salbutamol for exacerbations and severe exacerbations. By contrast, in patients with blood eosinophil counts of less than 0·15 × 109/L, exacerbations and severe exacerbations tended to be higher for maintenance budesonide plus as-needed salbutamol than for only as-needed salbutamol. There was no consistent interaction between treatment response and FeNO or the composite score. The beneficial effects of as-needed budesonide–formoterol compared with as-needed salbutamol were independent of biomarker profile.

Implications of all the available evidence

These findings are in keeping with consistent evidence in patients with more severe asthma and COPD that the blood eosinophil count is an independent prognostic marker of risk for exacerbations and a predictive biomarker of the response to maintenance ICS. The study supports the view that the measurement of blood eosinophils is an important component of risk assessment and treatment selection across the spectrum of obstructive lung diseases. Our findings show that the effects of as-needed budesonide–formoterol are independent of biomarker status.

The influence of biomarkers on response to treatment was a prespecified research question in a 12-month, open-label, parallel-group, randomised clinical trial11 of patients with mild asthma. In the trial, we compared as-needed salbutamol with maintenance budesonide plus as-needed salbutamol, and with as-needed budesonide–formoterol.11 We found no significant interaction between baseline blood eosinophil counts, serum periostin, or FeNO and the response to as-needed budesonide–formoterol when compared with the other treatments for exacerbations, severe exacerbations, or the 5-item Asthma Control Questionnaire (ACQ-5).11 We also previously reported the prognostic and predictive value of serum periostin12 and a three-way composite of blood eosinophil counts, FeNO, and periostin,11 but periostin was not included in the present analysis because work by us and others has shown that periostin varies substantially between races13 and has disappointing prognostic and predictive properties.14, 15

In this prespecified, secondary subgroup analysis, we aimed to test the hypothesis that in patients with mild asthma, higher blood eosinophil counts, FeNO, or their combination are associated with greater response to either of the treatments containing budesonide than to as-needed salbutamol for this cohort.

Section snippets

Study design

We used a 52-week, open-label, parallel-group, multicentre, phase 3, randomised controlled trial to evaluate three different treatment regimens for mild asthma. The study was done in 16 clinical trial units based in primary and secondary care centres in New Zealand, the UK, Italy, and Australia, all of which obtained approval by the relevant state and national ethics committees.11 All authors had full access to the raw data and no writing assistance was provided. Details of the protocol have

Results

This open-label, parallel-group, multicentre, phase 3, randomised controlled trial enrolled 675 participants between March 17, 2016, and Aug 29, 2017, with the last patient finishing treatment on Aug 30, 2018. The median follow-up was 52 weeks. Follow-up data were not available for 13 participants, but no participants were withdrawn by the sponsor. 11 patients who were randomly assigned to salbutamol were withdrawn because of treatment failure, as indicated by the addition of budesonide or

Discussion

The original open-label, randomised controlled trial11 represents the largest study to investigate the effect of different ICS regimens on exacerbations in patients with mild asthma, for whom information is available on biomarkers of eosinophilic airway inflammation. As such, it provides a unique opportunity to investigate whether individual biomarkers or their combination are associated with the risk of exacerbations in patients treated with as-needed salbutamol, compared with either

Data sharing

The complete de-identified patient dataset, statistical plan, and consent forms will be made available on request to RB ([email protected]) 1 year after publication, with no time limit. Data will be made available to researchers whose proposed use of the data has been approved by the Novel START Steering Committee. For a specified purpose, to achieve the aims outlined in the approved proposal. We will issue a signed data access agreement. Data can only be used to achieve the aims

References (30)

  • S Pascoe et al.

    Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial

    Lancet Respir Med

    (2019)
  • DB Price et al.

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

    Lancet Respir Med

    (2015)
  • LG Heaney et al.

    Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

    Thorax

    (2016)
  • M Castro et al.

    Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma

    N Engl J Med

    (2018)
  • ID Pavord et al.

    Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

    Thorax

    (2016)
  • Cited by (79)

    • The Role of ICS-Containing Rescue Therapy Versus SABA Alone in Asthma Management Today

      2024, Journal of Allergy and Clinical Immunology: In Practice
    • Toward a Predict and Prevent Approach in Obstructive Airway Diseases

      2023, Journal of Allergy and Clinical Immunology: In Practice
    • “As-Needed” Inhaled Corticosteroids for Patients With Asthma

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