Impact of Sex on Prediction of Asthma Attacks by Clinical Risk Factors and Type 2 Biomarkers

BACKGROUND: Multiple clinical and inflammatory risk factors for asthma attacks have been identified, including attack history, comorbidities, blood eosinophil count (BEC), and exhaled nitric oxide (Feno). However, the impact of sex on their prognostic value is unclear. RESEARCH QUESTION: Does sex modify prognostic values of clinical characteristics, BEC, and Feno for severe asthma attacks? STUDY DESIGN AND METHODS: We conducted a patient-level meta-analysis of the control arms of 22 randomized asthma trials (Oxford Asthma Attack Risk Scale Meta-Analysis [ORACLE2], N = 6,510). Annualized severe asthma attack rates and (adjusted) rate ratios (aRRs) (95% CI) were estimated with sex-specific multivariable negative binomial models, adjusting for baseline demographics, clinical characteristics, and type 2 biomarkers (BEC and Feno). Interaction tests evaluated the influence of sex on other prognostic factors. RESULTS: Among 4,140 female and 2,370 male patients, crude attack rates were higher in female patients than in male patients (0.90 vs 0.74 attacks/patient-year). Prior asthma attacks were the strongest predictor of future attacks in both sexes but with a higher aRR in male individuals (aRR [95%CI], 2.76 [1.97-3.88]) than in female individuals (1.66 [1.33-2.06]; interaction P = .03). In contrast, the prognostic utility of treatment intensity, BMI, lung function, smoking status, comorbidities, and type 2 biomarkers was similar in male and female individuals. The highest risk was seen in the combined high-BEC/high- Feno groups for both sexes. INTERPRETATION: To our knowledge, this study is the first patient-level meta-analysis of prospectively collected clinical trial data to evaluate sex as a modifier of prognostic factors for asthma attacks. The overall annualized asthma attack rate was higher in female than male individuals. Prior attack history had stronger prognostic value for future attacks in male individuals, whereas other clinical risk factors and type 2 biomarkers (blood eosinophils and Feno) showed no major sex differences. These findings highlight that female individuals without prior attacks may face increased risk, and they have important implications for clinical research and practice.