支气管扩张症中的嗜酸性粒细胞与2型炎症：从表型识别走向基于内型的治疗

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中文摘要

支气管扩张症日益被认为在生物学上具有异质性，但嗜酸性粒细胞及2型（T2）相关信号的临床意义仍不确定。本综述重新评估该领域是否已从对嗜酸性粒细胞表型的认识，进展为支气管扩张症特异、具有治疗可操作性的T2内型。血嗜酸性粒细胞计数（BEC）、气道嗜酸性粒细胞增多、呼出气一氧化氮分数、总免疫球蛋白E以及通路水平特征所捕捉的是相互重叠但并不等同的特征。当前证据对嗜酸性粒细胞表型的支持强于对统一的支气管扩张症特异性T2内型的支持。气道研究证实部分患者存在嗜酸性粒细胞活化，但支持完整且可重复的上皮警报素-T2细胞-IL-4/IL-5/IL-13通路的直接证据有限，且哮喘、变应性支气管肺曲霉病、真菌致敏、慢性鼻窦炎和慢性阻塞性肺疾病均可干扰生物标志物的解读。预后关联呈非线性且依赖具体情境：在不同情境下，持续性或高嗜酸性粒细胞增多以及极低BEC均曾与不良结局相关。吸入性糖皮质激素显示出生物学效应及探索性的嗜酸性粒细胞相关应答信号，但这些并不能验证BEC作为预测性生物标志物，也不支持仅因BEC升高而进行治疗。在MAHALE研究中，贝那利珠单抗造成嗜酸性粒细胞深度耗竭，但在所研究人群中未显示出临床疗效；严重招募不足及嗜酸性粒细胞富集有限，限制了对持续性嗜酸性粒细胞疾病作出推断。来自合并支气管扩张症的重度哮喘生物制剂治疗证据，对支气管扩张症疗效而言仍属间接。因此，本综述界定了在表型识别能够指导治疗选择之前所需的验证路径：重复的稳定期表型评估、气道生物学验证、与T2共病的区分、预先设定的治疗-by-生物标志物交互作用分析，以及有足够把握度的生物标志物富集试验。

英文摘要

Bronchiectasis is increasingly recognized as biologically heterogeneous, yet the clinical meaning of eosinophilic and type 2 (T2)-associated signals remains uncertain. This review reassesses whether the field has progressed from recognition of an eosinophilic phenotype to a bronchiectasis-specific, therapeutically actionable T2 endotype. Blood eosinophil count (BEC), airway eosinophilia, fractional exhaled nitric oxide, total immunoglobulin E, and pathway-level signatures capture overlapping but non-equivalent features. Current evidence supports an eosinophilic phenotype more strongly than a unified bronchiectasis-specific T2 endotype. Airway studies confirm eosinophil activation in selected patients, but direct evidence for a complete and reproducible epithelial alarmin-T2-cell-IL-4/IL-5/IL-13 pathway is limited, and asthma, allergic bronchopulmonary aspergillosis, fungal sensitization, chronic rhinosinusitis, and chronic obstructive pulmonary disease can confound biomarker interpretation. Prognostic associations are non-linear and context dependent: persistent or high eosinophilia and very low BEC have each been associated with adverse outcomes in different settings. Inhaled corticosteroids show biological effects and exploratory eosinophil-associated response signals, but these do not validate BEC as a predictive biomarker or support treatment solely for elevated BEC. In MAHALE, benralizumab produced profound eosinophil depletion without demonstrated clinical efficacy in the population studied; severe under-recruitment and limited eosinophilic enrichment restrict inference for persistently eosinophilic disease. Evidence from biologic-treated severe asthma with coexisting bronchiectasis remains indirect for bronchiectasis efficacy. The review therefore defines the validation pathway required before phenotype recognition can inform treatment selection: repeated stable-state phenotyping, airway biological validation, separation from T2 comorbidities, prespecified treatment-by-biomarker interaction analyses, and adequately powered biomarker-enriched trials.