性别不影响临床风险因素和2型生物标志物对哮喘急性发作的预测价值
2026/02/25
摘要
背景： 目前已明确多个哮喘急性发作的临床和炎症性风险因素，包括急性发作史、合并症、血嗜酸性粒细胞计数和呼出气一氧化氮（FENO）。然而，性别对其预后价值的影响尚不清楚。
研究问题：性别是否修饰临床特征、血嗜酸性粒细胞计数和FENO对重度哮喘急性发作的预后价值？
研究设计和方法：作者对22项随机哮喘试验的对照组进行了患者层面荟萃分析（ORACLE2项目，总样本量N=6,510）。采用基于性别的多变量负二项回归模型，校正基线人口学特征、临床特征和2型生物标志物（血嗜酸性粒细胞计数和FENO），评估年化重度哮喘急性发作率及（校正后）比率比及其95%置信区间。通过交互作用检验评估性别对其他预后因素的影响。
结果：在4,140名女性和2,370名男性中，女性的粗急性发作率高于男性（0.90次/患者年 vs. 0.74次/患者年）。既往哮喘急性发作史是两性未来急性发作的最强预测因子，但男性的校正后比率比高于女性（男性：2.76 [1.97-3.88]；女性：1.66 [1.33-2.06]；交互作用p=0.03）。相比之下，治疗强度、体重指数、肺功能、吸烟状况、合并症和2型生物标志物在男性和女性中的预后价值相似。两性中，血嗜酸性粒细胞计数和FENO双高的组合组显示出最高的急性发作风险。
结论：本研究是首个基于前瞻性收集的临床试验数据进行患者层面荟萃分析，以评估性别是否修饰哮喘急性发作预后因素的研究。女性的总体年化哮喘急性发作率高于男性。既往急性发作史对男性未来发作的预后价值更强，而其他临床风险因素和2型生物标志物（血嗜酸性粒细胞和FENO）未显示显著的性别差异。这些发现提示，无既往急性发作史的女性仍可能面临增加的发作风险，对临床研究和实践具有重要启示。
关键词：哮喘；呼出气一氧化氮分数；LIST；生物标志物；血嗜酸性粒细胞；急性发作；荟萃分析
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 (ORACLE2, N=6,510). Annualised severe asthma attack rates and (adjusted) rate ratios (aRR) [95% confidence intervals (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 women and 2,370 men, crude attack rates were higher in women than in men (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 adjusted RR in men (aRR [95%CI]: 2.76 [1.97-3.88]) than women (1.66 [1.33-2.06]; interaction p=0.03). In contrast, the prognostic utility of treatment intensity, body mass index, lung function, smoking status, comorbidities and type-2 biomarkers was similar in males and females. The highest risk was seen in the combined high-BEC/high-FeNO groups for both sexes.
Interpretation: 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 annualised asthma attack rate was higher in women than men. Prior attack history had stronger prognostic value for future attacks in men, while other clinical risk factors and type-2 biomarkers (blood eosinophils and FeNO) showed no major sex differences. These findings highlight that women without prior attacks may still face increased risk and have important implications for clinical research and practice.
Keywords: Asthma; FeNO; LIST; biomarkers; blood eosinophils; exacerbation; meta-analysis.
背景： 目前已明确多个哮喘急性发作的临床和炎症性风险因素，包括急性发作史、合并症、血嗜酸性粒细胞计数和呼出气一氧化氮（FENO）。然而，性别对其预后价值的影响尚不清楚。
研究问题：性别是否修饰临床特征、血嗜酸性粒细胞计数和FENO对重度哮喘急性发作的预后价值？
研究设计和方法：作者对22项随机哮喘试验的对照组进行了患者层面荟萃分析（ORACLE2项目，总样本量N=6,510）。采用基于性别的多变量负二项回归模型，校正基线人口学特征、临床特征和2型生物标志物（血嗜酸性粒细胞计数和FENO），评估年化重度哮喘急性发作率及（校正后）比率比及其95%置信区间。通过交互作用检验评估性别对其他预后因素的影响。
结果：在4,140名女性和2,370名男性中，女性的粗急性发作率高于男性（0.90次/患者年 vs. 0.74次/患者年）。既往哮喘急性发作史是两性未来急性发作的最强预测因子，但男性的校正后比率比高于女性（男性：2.76 [1.97-3.88]；女性：1.66 [1.33-2.06]；交互作用p=0.03）。相比之下，治疗强度、体重指数、肺功能、吸烟状况、合并症和2型生物标志物在男性和女性中的预后价值相似。两性中，血嗜酸性粒细胞计数和FENO双高的组合组显示出最高的急性发作风险。
结论：本研究是首个基于前瞻性收集的临床试验数据进行患者层面荟萃分析，以评估性别是否修饰哮喘急性发作预后因素的研究。女性的总体年化哮喘急性发作率高于男性。既往急性发作史对男性未来发作的预后价值更强，而其他临床风险因素和2型生物标志物（血嗜酸性粒细胞和FENO）未显示显著的性别差异。这些发现提示，无既往急性发作史的女性仍可能面临增加的发作风险，对临床研究和实践具有重要启示。
关键词：哮喘；呼出气一氧化氮分数；LIST；生物标志物；血嗜酸性粒细胞；急性发作；荟萃分析
（南方医科大学南方医院 羊洁 赵文驱 赵海金）
（Riemann S,et al. Sex does not modify prediction of asthma attacks by clinical risk factors and Type-2 biomarkers Chest. 2026 Jan 30:S0012-3692(26)00131-5.）
Abstract（Riemann S,et al. Sex does not modify prediction of asthma attacks by clinical risk factors and Type-2 biomarkers Chest. 2026 Jan 30:S0012-3692(26)00131-5.）
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 (ORACLE2, N=6,510). Annualised severe asthma attack rates and (adjusted) rate ratios (aRR) [95% confidence intervals (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 women and 2,370 men, crude attack rates were higher in women than in men (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 adjusted RR in men (aRR [95%CI]: 2.76 [1.97-3.88]) than women (1.66 [1.33-2.06]; interaction p=0.03). In contrast, the prognostic utility of treatment intensity, body mass index, lung function, smoking status, comorbidities and type-2 biomarkers was similar in males and females. The highest risk was seen in the combined high-BEC/high-FeNO groups for both sexes.
Interpretation: 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 annualised asthma attack rate was higher in women than men. Prior attack history had stronger prognostic value for future attacks in men, while other clinical risk factors and type-2 biomarkers (blood eosinophils and FeNO) showed no major sex differences. These findings highlight that women without prior attacks may still face increased risk and have important implications for clinical research and practice.
Keywords: Asthma; FeNO; LIST; biomarkers; blood eosinophils; exacerbation; meta-analysis.
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