NEW evidence from a large meta-analysis of randomised controlled trials (RCTs) confirms that type 2 inflammatory biomarkers, specifically blood eosinophil count and fractional exhaled nitric oxide (FeNO), significantly enhance prognostic assessment of asthma attack risk, offering clinicians a more refined approach to risk stratification and treatment targeting.
This systematic review and individual patient data meta-analysis, part of the ORACLE2 study, examined trials published between 1993–2021 that investigated asthma attack rates in patients aged 12 years or older under stable treatment regimens. Eligible studies included those reporting baseline blood eosinophil count and FeNO. Two reviewers independently screened studies, with disagreements adjudicated by a panel of five.
From 976 initial studies, 23 RCTs were ultimately included. Individual patient data were obtained from 22 RCTs, totalling 6513 participants. The primary outcome was the rate of severe asthma attacks (≥3 days of systemic corticosteroid use) over a minimum of 6 months. Negative binomial models adjusted for key covariates were used to evaluate associations, with further analyses examining interactions between inflammatory biomarkers. Certainty of evidence was appraised using GRADE, and study heterogeneity was quantified using the concordance statistic.
Among 5,482 person-years of follow-up, 4,615 severe asthma attacks occurred, yielding an annualised rate of 0.84 per person-year. Higher blood eosinophil count and FeNO were each associated with increased risk of attack (rate ratio [RR] per 10-fold increase: 1.48, 95% CI: 1.30–1.68 for eosinophils; 1.44, 1.26–1.65 for FeNO). When combined, these biomarkers conferred greater predictive value than either alone.
Additional significant predictors included prior attack history (RR: 1.94, 1.61–2.32), severe versus moderate disease (RR: 1.57, 1.22–2.03), reduced FEV1% (RR: 1.11 per 10% decrease, 1.08–1.15), and higher ACQ-5 scores (RR: 1.10 per 0.5-point increase, 1.07–1.13). Conversely, bronchodilator reversibility was inversely associated with risk (RR: 0.93 per 10% increase, 0.90–0.96), primarily between 0–25%.
This robust analysis confirms that type 2 biomarkers, specifically blood eosinophils and FeNO, provide additive prognostic value for predicting asthma attacks. Incorporating these biomarkers into routine clinical assessment may enhance personalised asthma management and inform more precise therapeutic strategies.
Reference
Meulmeester FL et al. Inflammatory and clinical risk factors for asthma attacks (ORACLE2): a patient-level meta-analysis of control groups of 22 randomised trials. Lancet Respir Med. 2025; DOI: 10.1016/S2213-2600(25)00037-2.
