重叠综合征（COPD-阻塞性睡眠呼吸暂停）中的精准医学：从表型和内型到可治疗特征

文献信息

中文摘要

引言： COPD-OSA重叠综合征（OVS）定义为同一患者中慢性阻塞性肺疾病与阻塞性睡眠呼吸暂停综合征共存；在接受任一疾病评估的患者中占28.3%，并且与任一单独疾病相比，死亡率显著更高。当前的治疗方法，包括PAP治疗和支气管扩张，将该综合征视为同质实体，忽视了该患者群体的生物学异质性。
目的： 本综述提出一个系统框架，用于对COPD与OSA之间生物学相互作用进行内型分类，整合当前关于OVS潜在病理生理机制、临床可及生物标志物和新兴疗法的文献。
方法： 基于现有文献的叙述性综述，聚焦于2010年至2026年间发表的研究，通过PubMed、PMC和Dove Medical Press检索，使用以下术语：COPD-OSA重叠综合征、内型、精准医学、表型、生物标志物、dupilumab和基于肠促胰岛素的疗法。
结果： 提出了四种临床表型（肥胖-代谢型、肺气肿型、支气管炎-低氧型和高碳酸血症型）和三种分子内型（Th2/嗜酸性粒细胞型、中性粒细胞/氧化型和代谢-脂肪因子型），每种均具有独特的病理生理机制和特定的治疗意义。两种疾病之间的相互作用产生了一种独特且显著的低氧血症特征。我们提出“双重打击低氧血症”模型作为概念框架，其特征是与任一单独疾病相比，全身炎症放大和心血管风险增加。该提出的模型尚未经过前瞻性验证。Dupilumab（已获批用于COPD患者中以嗜酸性粒细胞计数≥300个/μL为特征的炎症表型）代表一种有前景的选择，尽管目前在OVS人群中尚无支持，但仍可能与该综合征的Th2/嗜酸性粒细胞内型相关；而tirzepatide（在SURMOUNT-OSA试验中，与安慰剂相比，在肥胖和中重度OSA患者中而非确诊OVS患者中，将AHI最多降低23.8次/小时）可能代表一种有前景的疗法，用于肥胖OVS患者的代谢-脂肪因子内型。一个最小生物标志物组合，包括血嗜酸性粒细胞、FeNO、日间PaCO2、BMI和T90，为识别主导内型提供了一种实用方法。
结论： OVS的内型分型可能提供一个框架，超越统一的治疗方法，转向基于主导潜在生物学机制的更个体化管理。聚焦于内型分层和OVS队列的随机临床试验仍是研究重点。

英文摘要

INTRODUCTION: COPD-OSA overlap syndrome (OVS) is defined by the coexistence of chronic obstructive pulmonary disease and obstructive sleep apnea syndrome in the same patient; it affects 28.3% of patients evaluated for either condition and is associated with significantly higher mortality compared to either pathology in isolation. Current therapeutic approaches, involving PAP therapy and bronchodilation, treat this syndrome as a homogeneous entity and ignore the biological heterogeneity of this patient population.
OBJECTIVES: This review proposes a systematic framework for the endotypic classification of biological interactions between COPD and OSA, integrating current literature on the pathophysiological mechanisms underlying the OVS, clinically accessible biomarkers, and emerging therapies.
METHODS: A narrative review based on available literature, focusing on studies published between 2010 and 2026 identified via searches in PubMed, PMC, and Dove Medical Press using the terms: COPD-OSA overlap syndrome, endotype, precision medicine, phenotype, biomarker, dupilumab, and incretin-based therapies.
RESULTS: Four clinical phenotypes (obese-metabolic, emphysematous, bronchitic-hypoxemic, and hypercapnic) and three molecular endotypes (Th2/eosinophilic, neutrophilic/oxidative, and metabolic-adipokine) are proposed, each with distinct pathophysiological mechanisms and specific therapeutic implications. The interaction between the two conditions generates a unique, pronounced hypoxemic profile. We propose the "double-hit hypoxemia" model as a conceptual framework characterized by amplified systemic inflammation and increased cardiovascular risk compared to either pathology in isolation. This proposed model has not yet been prospectively validated. Dupilumab (approved for an inflammatory phenotype in COPD patients characterized by eosinophil counts ≥ 300 cells/μL) represents a promising option, though currently unsupported in the OVS population, that could nonetheless be relevant to the Th2/eosinophilic endotype of this syndrome and tirzepatide (which reduced the AHI by up to 23.8 events/hour versus placebo in the SURMOUNT-OSA trial, conducted in patients with obesity and moderate-to-severe OSA, rather than in patients with confirmed OVS) could represent a promising therapy for the metabolic-adipokine endotype of obese patients with OVS. A minimal biomarker panel, comprising blood eosinophils, FeNO, daytime PaCO2, BMI, and T90, allows for a practical approach to identifying the dominant endotype.
CONCLUSIONS: Endotyping of OVS may provide a framework for moving beyond a uniform therapeutic approach toward more individualized management based on the dominant underlying biological mechanism. Randomized clinical trials focusing on endotypic stratification and OVS cohorts remain research priorities.