慢性阻塞性肺疾病加重期的早期诊断生物标志物：探索性、前瞻性、纵向、单中心、观察性 MARKED 研究方案。

Early diagnostic BioMARKers in exacerbations of chronic obstructive pulmonary disease: protocol of the exploratory, prospective, longitudinal, single-centre, observational MARKED study.

机构信息

Department of Research and Development, CIRO, Horn, Netherlands

Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health Medicine and Life Sciences, Maastricht University Medical Centre+, Maastricht, Netherlands.

出版信息

BMJ Open. 2023 Mar 3;13(3):e068787. doi: 10.1136/bmjopen-2022-068787.

DOI:10.1136/bmjopen-2022-068787

PMID:36868599

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9990620/

Abstract

INTRODUCTION

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) play a pivotal role in the burden and progressive course of chronic obstructive pulmonary disease (COPD). As such, disease management is predominantly based on the prevention of these episodes of acute worsening of respiratory symptoms. However, to date, personalised prediction and early and accurate diagnosis of AECOPD remain unsuccessful. Therefore, the current study was designed to explore which frequently measured biomarkers can predict an AECOPD and/or respiratory infection in patients with COPD. Moreover, the study aims to increase our understanding of the heterogeneity of AECOPD as well as the role of microbial composition and hostmicrobiome interactions to elucidate new disease biology in COPD.

METHODS AND ANALYSIS

The 'Early diagnostic BioMARKers in Exacerbations of COPD' study is an exploratory, prospective, longitudinal, single-centre, observational study with 8-week follow-up enrolling up to 150 patients with COPD admitted to inpatient pulmonary rehabilitation at Ciro (Horn, the Netherlands). Respiratory symptoms, vitals, spirometry and nasopharyngeal, venous blood, spontaneous sputum and stool samples will be frequently collected for exploratory biomarker analysis, longitudinal characterisation of AECOPD (ie, clinical, functional and microbial) and to identify host-microbiome interactions. Genomic sequencing will be performed to identify mutations associated with increased risk of AECOPD and microbial infections. Predictors of time-to-first AECOPD will be modelled using Cox proportional hazards' regression. Multiomic analyses will provide a novel integration tool to generate predictive models and testable hypotheses about disease causation and predictors of disease progression.

ETHICS AND DISSEMINATION

This protocol was approved by the Medical Research Ethics Committees United (MEC-U), Nieuwegein, the Netherlands (NL71364.100.19).

TRIAL REGISTRATION NUMBER

NCT05315674.

摘要

简介

慢性阻塞性肺疾病（COPD）的急性加重（AECOPD）在 COPD 的负担和进展过程中起着关键作用。因此，疾病管理主要基于预防这些呼吸症状急性恶化的情况。然而，迄今为止，AECOPD 的个体化预测和早期、准确诊断仍未成功。因此，本研究旨在探索哪些经常测量的生物标志物可以预测 COPD 患者的 AECOPD 和/或呼吸道感染。此外，本研究旨在增加我们对 AECOPD 异质性的认识，以及微生物组成和宿主-微生物相互作用的作用，以阐明 COPD 中的新疾病生物学。

方法和分析

“AECOPD 中早期诊断生物标志物”研究是一项探索性、前瞻性、纵向、单中心、观察性研究，对 150 名入住荷兰霍恩 Ciro 住院肺康复的 COPD 患者进行为期 8 周的随访。经常采集呼吸症状、生命体征、肺活量测定和鼻咽、静脉血、自发性痰液和粪便样本进行探索性生物标志物分析、AECOPD 的纵向特征（即临床、功能和微生物），并确定宿主-微生物相互作用。将进行基因组测序，以鉴定与 AECOPD 和微生物感染风险增加相关的突变。使用 Cox 比例风险回归模型对首次 AECOPD 的时间预测因素进行建模。多组学分析将提供一种新的整合工具，以生成关于疾病因果关系和疾病进展预测因素的预测模型和可测试的假设。