Evaluating symptom burden to characterise, predict, and prevent asthma attacks: a patient-level analysis of randomised trials and translational prospective studies

Journal article

Background:
Asthma symptoms often guide assessment and management, yet their prognostic and predictive value remains unclear. We evaluated the extent to which symptom burden measured by the 5-item Asthma Control Questionnaire (ACQ-5) predicts future severe asthma attacks and response to anti-inflammatory therapy.
Methods:
Primary analyses used the ORACLE2 patient-level meta-analysis (n=6,513) of control arm participants from 22 randomised controlled trials. Additional datasets included the DREAM intravenous mepolizumab arm (n=461); a cross-sectional severe asthma cohort (n=74); and two acute asthma cohorts (PRISMA, biologic-naïve, n=53; BOOST, anti-interleukin-5-treated, n=60). Associations between baseline ACQ-5 and clinical, physiological, and inflammatory profiles, asthma attack risk, and anti-inflammatory treatment responses were examined.
Findings:
Across five datasets encompassing 7,161 distinct participants, asthma severity, lung function, inflammatory profiles, comorbidities, and ACQ-5 varied widely. The proportion of subjects with high symptom burden (ACQ-5>1.5) ranged from 39% to 100%. Baseline ACQ-5 showed no consistent cross-sectional association with other clinical, physiological, or inflammatory asthma features. Each 0.5-point increase in baseline ACQ-5 was associated with a modest increase in future asthma attacks (adjusted rate ratio [aRR] 1.09, 95%CI 1.06-1.12; ΔR² =0.02 versus multivariable prediction model without ACQ-5). Baseline ACQ-5 did not alter relative and absolute attack risk reduction from intravenous mepolizumab in DREAM. In contrast, patients with high blood eosinophils and exhaled nitric oxide (FeNO) had the highest relative and absolute risk reduction (2.81 vs 1.17 attacks; aRR 0.38, 95%CI 0.25-0.57). In PRISMA and BOOST, ACQ-5 was not associated with post-corticosteroid lung function change. Across studies, relative and absolute treatment effects showed consistent associations with blood eosinophils and FeNO.
Conclusions:
In a large patient-level analysis of RCTs and translational prospective studies, we observed limited alignment of symptom burden with other clinical, physiological, or biological features of asthma and modest prognostic value for severe attacks. In contrast, type-2 biomarkers more reliably identified high-risk and treatment-responsive patients. Symptoms may require contextual interpretation to guide anti-inflammatory escalation in asthma.
Registration:
PROSPERO#CRD42021245337,NCT#02717689;NCT#01000506,NCT#05870215

Authors: Couillard, S; Meulmeester, FL; Charland, P; Lemaire-Paquette, S; Howell, I

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Lancet Respiratory Medicine
• Acceptance date: 2026-04-30
• EISSN: 2213-2619
• ISSN: 2213-2600
• Language: English
• Keywords: airways; asthma; biomarkers; eosinophils; exacerbations; FeNO; meta-analysis; predictions; prognosis; symptoms; type-2 inflammation