Female patients with asthma had a higher annualized severe attack rate than male patients, yet the prognostic utility of type 2 biomarkers — blood eosinophil count and fractional exhaled nitric oxide — did not differ significantly by sex, according to a patient-level meta-analysis published in CHEST.
The ORACLE2 (OxfoRd Asthma attaCk risk scaLE Meta-Analysis) analysis evaluated 6,510 patients aged 12 years or older from the control arms of 22 randomized controlled trials. Of these, 4,140 (64%) were female and 2,370 (36%) were male. Annualized severe asthma attack rates — defined as attacks requiring 3 or more days of systemic corticosteroids — were 0.90 attacks per patient-year in female patients vs 0.74 in male patients.
Attack History
Prior asthma attack history was the strongest predictor of future attacks in both sexes, but its prognostic strength differed by sex. The adjusted rate ratio for any attack in the preceding 12 months was higher in male patients than in female patients, representing a sex-basedinteraction.
Researchers suggested this difference reflects a relatively higher baseline attack risk among female patients without a recent attack history, meaning the absence of a recent exacerbation may be less reassuring in female patients. They noted that more remote attack history may also contribute to risk.
All other clinical risk factors — including treatment intensity, body mass index, lung function, smoking status, and comorbidities — showed similar prognostic associations across sexes.
Type 2 Biomarker Stratification
In both sexes, higher biomarker levels were associated with higher attack rates. Patients with both elevated fractional exhaled nitric oxide and elevated blood eosinophil count had the highest risk, whereas those with low levels of both biomarkers had the lowest risk.
Interaction analyses showed no meaningful sex-based differences in how these biomarkers predicted asthma attacks, whether evaluated individually or in combination.
Male patients had slightly higher baseline fractional exhaled nitric oxide and blood eosinophil levels than female patients, but increases in these biomarkers were associated with similar increases in attack risk across sexes.
Baseline Differences and Higher Risk in Female Patients
Female patients were slightly older and had higher body mass index, along with higher rates of psychiatric disease and severe obesity. Asthma control was also poorer in female patients, with higher symptom scores and a greater proportion reporting severe attacks in the prior year.
During 1 year of follow-up, 38% of female patients vs 31% of male patients experienced at least one severe asthma attack.
After adjustment for key clinical variables, the difference in time to first attack between sexes was substantially reduced, suggesting that baseline risk factors may account for part of the higher observed risk in female patients rather than differences in how individual risk factors operate.
Obesity and Clinical Trial Implications
Patients with severe obesity had the highest attack rates in both sexes, although the prognostic effect of body mass index was similar between female and male patients.
Researchers noted that patients with severe obesity are sometimes excluded from clinical trials, despite representing a high-risk population. They suggested future studies either include these patients more consistently or design trials specifically targeting this subgroup.
The findings also have implications for trial design. Because many asthma trials enroll more female patients, differences in baseline risk factors may influence observed outcomes in control groups. Researchers suggested that sex-stratified randomization may help address this imbalance.
Limitations
The analysis was restricted to control arms of randomized trials, which may introduce placebo-related effects. Data on gender identity were not available, and only sex at birth was analyzed. The subgroup of patients with severe obesity was relatively small, and active treatment arms were not included, limiting assessment of treatment response differences.
Bottom Line
Biomarker-guided risk stratification using blood eosinophil count and fractional exhaled nitric oxide can be applied similarly in female and male patients. However, female patients without a recent asthma attack may still face elevated risk and should not be considered low risk based on attack history alone.
Disclosures
Multiple researchers reported financial relationships with pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron, Novartis, and Genentech, in the form of speaker honoraria, consulting fees, research grants, or employment. Full disclosures are available in the published article.
The study is published in CHEST.
