Blood eosinophils, fractional exhaled nitric oxide and the risk of asthma attacks in randomised controlled trials: protocol for a systemic review and control arm patient-level meta-analysis for clinical prediction modelling

Abstract

Introduction: The reduction of the risk of asthma attacks is a major goal of guidelines. The fact that type-2 inflammatory biomarkers identify a higher risk, anti-inflammatory responsive phenotype is potentially relevant to this goal. We aim to quantify the relation between blood eosinophils, exhaled nitric oxide (FeNO) and the risk of severe asthma attacks.

Methods and analysis: A systematic review of randomised controlled trials (RCTs) will be conducted by searching MEDLINE from January 1993 to April 2021. We will include RCTs that investigated the effect of fixed treatment(s) regimen(s) on severe asthma exacerbation rates over at least 24 weeks and reported a baseline value for blood eosinophils and FeNO. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for RCTs. Study authors will be contacted to request anonymised individual participant data (IPD) for patients randomised to the trial's control arm. An IPD meta-analysis will be performed for multivariable prognostic modelling with performance assessment (calibration plots and the c-statistic) in a cross-validation by study procedure. The outcome to predict is the absolute number of severe asthma attacks to occur in the following 12 months if anti-inflammatory therapy is not changed (ie, annualised number of attacks requiring ≥3 days of systemic corticosteroids and/or hospitalisation if the patient was randomised to the control arm of an RCT). A summary prognostic equation and risk stratification chart will be reported as a basis for further analyses of individualised treatment benefit.

Ethics and dissemination: The protocol has been reviewed by the relevant Oxford academic ethics committee and found to comprise fully anonymised data not requiring further ethical approbation. Results will be communicated in an international meeting and submitted to a peer-reviewed journal.

Prospero registration number: CRD42021245337.

Keywords: asthma; epidemiology; immunology; preventive medicine; thoracic medicine.

Figure 1

The prototype OxfoRd Asthma attaCk risk scaLE (ORACLE). Numbers in each cell are predicted annual asthma attack rates for patients over the age of 12 if treatment is not changed. An asthma attack is an episode of acute asthma requiring treatment with systemic steroids ≥3 days and/or hospitalisation. The blood eosinophil count is contemporaneous or the highest result in last 12 months; fractional exhaled nitric oxide level (FeNO) is contemporaneous. *Risk factors are defined by the Global Initiative for Asthma (GINA) guidelines: poor symptom control (Asthma Control Questionnaire score ≥1.5), low lung function (forced expiratory volume in 1 s <80% predicted), adherence issues, reliever over-use (>200 dose salbutamol cannister/month), intubation or intensive care unit admission for asthma previously, comorbidities (one of: chronic rhinosinusitis, obesity, psychiatric disease), environmental exposures (one of: smoking, allergen, pollution). Reproduced from Couillard et al with permission under the original CC BY public copyright license.