Inflammatory and clinical prognostic factors for asthma attacks: a patient-level meta-analysis of control arms of 22 randomised trials

Background: Clinical risk factors for severe asthma attacks have been identified, but their incremental prognostic values remain unclear. Additionally, the independent contribution of type-2 inflammation, a common, treatable process, is undetermined. We aimed to quantify the prognostic value of baseline characteristics and type-2 inflammatory biomarkers, specifically blood eosinophil count (BEC) and exhaled nitric oxide (FeNO), to predict asthma attacks. Methods: We conducted a systematic review of randomised controlled trials (RCTs) in MEDLINE (1-Jan-1993 to 1-Apr-2021). We investigated the rate of severe asthma attacks (≥3 days systemic corticosteroids) over ≥6 months and prognostic effects of baseline BEC and FeNO in control arm participants. Individual patient data were obtained for meta-analysis from 22 RCTs (n=6,513). Rate ratios (RR) with 95% confidence intervals were derived for annualised asthma attack rates from negative binomial models adjusted for key variables including type-2 biomarkers, exploring interactions between BEC and FeNO. Certainty of evidence was assessed using GRADE. PROSPERO#:CRD42021245337. Findings: Most patients (n=5,972/6,513, 92%) had moderate-to-severe asthma; 4,615 attacks occurred during 5,482 person·years follow-up (annualised asthma attack rate 0·84/p·yr). Both higher BEC or FeNO were linked to higher asthma attack risk (per 10-fold higher values, RR: 1·48 [1·30–1·68] and 1·44 [1·26–1·65)], respectively; high-certainty evidence). Other prognostic factors were attack history (yes/no, RR: 1·94 [1·61–2·32]); disease severity (severe-vs-moderate, RR: 1·57 [1·22–2·03]); FEV1% (per 10% decrease, RR: 1·11 [1·08–1·15]); and ACQ-5 (per 0·5 increase, RR: 1·10 [1·07–1·13])(high certainty). High BEC and high FeNO were associated with greater risk than either prognostic factor separately. Bronchodilator reversibility was associated with lower risk (per 10% increase, RR: 0·93 [0·90–0·96]; moderate certainty), with the reduction observed primarily between 0% and 25%. Interpretation: Blood eosinophils, FeNO, asthma attack history, disease severity, lower lung function, and symptoms are key predictors of asthma attacks. Conversely, we found that moderate bronchodilator reversibility was associated with reduced risk. These findings support incorporating BEC and FeNO into clinical risk stratification for targeted risk reduction. More individualised clinical decision-making models should be explored. Funding: NIHR,AIRS,APQ,AcMedSci,SAB,LUF