The C-BRIDGE Study: China Bronchiectasis Research Involving Databases, Genomics, and Endotyping

Обзор

Bronchiectasis is a heterogeneous airway disease with diverse causes, making precise diagnosis, prognosis, and treatment response prediction challenging. Identifying patient subgroups (phenotypes) and molecular profiles (endotypes) can enhance individualized assessment and management. While prior studies, primarily in European populations, have identified key phenotypes and endotypes, their relevance to Chinese patients remains unclear due to geographic and clinical differences. Specific causes of bronchiectasis, such as allergic bronchopulmonary aspergillosis (ABPA) and primary ciliary dyskinesia (PCD), may also exhibit distinct pathophysiology requiring further exploration. The C-BRIDGE Study seeks to characterize phenotypes and endotypes in Chinese bronchiectasis patients during stable disease and exacerbations, evaluate differences in clinical outcomes across these subgroups, and develop personalized medicine strategies based on these findings, applicable in China and globally. Primary Objective: To identify molecular endotypes of bronchiectasis that accurately predict prognosis and guide treatment responses. Secondary Objectives: To characterize molecular endotypes of stable bronchiectasis in Chinese patients. To define molecular endotypes of bronchiectasis exacerbations in Chinese patients. To investigate molecular endotypes specific to allergic bronchopulmonary aspergillosis (ABPA). To explore genotypes and inflammatory endotypes of cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) in Chinese patients. To validate candidate biomarkers for stable and exacerbation endotypes to support stratified medicine. To conduct in vivo or in vitro proof-of-concept studies using phenotypic data to identify patient subgroups likely to benefit from specific pharmacological interventions. Study Design: This observational cohort study will link identified patient subgroups with meaningful clinical outcomes to inform prognosis and optimize treatment strategies.

Подробное описание

Bronchiectasis is a common, heterogeneous chronic airway disease that remains understudied in clinical and translational research. Although several phenotypes and endotypes have been identified-primarily in European populations-data from Chinese patients are limited. Racial and geographic differences suggest that bronchiectasis phenotypes and endotypes in China may differ from those in Western cohorts. Recent controlled trials have failed to meet primary endpoints, likely due to insufficient identification of patient subgroups that optimally respond to antibiotics, mucoactive agents, or anti-inflammatory therapies. The C-BRIDGE Study seeks to address this gap by exploring the clinical, genomic, microbiological, inflammatory, and functional heterogeneity of bronchiectasis in Chinese patients to define molecular endotypes for stratified assessment and management.

Study Aims and Objectives:

1. Characterize molecular endotypes of stable bronchiectasis in Chinese patients. 2. Identify molecular endotypes of bronchiectasis exacerbations in Chinese patients. 3. Investigate molecular endotypes in patients with allergic bronchopulmonary aspergillosis (ABPA). 4. Develop a screening algorithm and elucidate genotypes and inflammatory endotypes of cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) in China. 5. Validate candidate biomarkers for stable and exacerbation endotypes to enable stratified medicine. 6. Perform in vivo and in vitro proof-of-concept studies using phenotypic data to pinpoint patient subgroups likely to benefit from specific pharmacological treatments.

Study Design:

Observational cohort study.

Study Methods:

A target of 1,500 patients with bronchiectasis will be recruited across participating centers for an observational study with the following aims:

Aim 1: Stable Disease Endotyping Up to 1,500 patients will be studied to define and validate endotypes of stable bronchiectasis. Data collection will include clinical assessments, sputum and nasal microbiome analysis, sputum proteomics, nasal and airway transcriptomics, single-cell sequencing of bronchoalveolar lavage fluid (BALF), and measurement of inflammatory markers in systemic, nasal, sputum, and BALF samples. A sub-study (n=100) will use air-liquid interface cultures of primary airway epithelial cells to assess responses to various stimuli and pharmacological interventions.

Aim 2: Exacerbation Endotyping A subset of 200 patients will be evaluated during exacerbations to replicate the phenotyping approach. This will involve analyzing changes from baseline in microbiome, proteomics, metabolomics, and other markers to identify clusters linked to exacerbation onset, progression, and outcomes.

Aim 3: Allergic Bronchopulmonary Aspergillosis (ABPA) Subgroup Analysis A subset of 150 patients with ABPA will be studied to investigate molecular endotypes by integrating single-cell sequencing, microbiome, mycobiome, proteomics, metabolomics, and other markers to identify clusters associated with exacerbation, recurrence, and treatment responses.

Aim 4: Idiopathic Bronchiectasis and Genetic Screening Patients with idiopathic bronchiectasis will be screened for cystic fibrosis, CFTR-related disorders, and primary ciliary dyskinesia (PCD) to identify genotypes and inflammatory endotypes. This will integrate genomics, microbiome, proteomics, and metabolomics to explore associations among phenotypes, genotypes, endotypes, and prognosis.

Aim 5: Biomarker Validation and Prediction Model Development Candidate phenotypes and endotypes will be externally validated using registered, ethically approved biobanks. Validated biomarkers will be correlated with clinically meaningful outcomes, such as treatment responses, to enable their use in stratified medicine. Clinical data and validated biomarkers will be integrated to construct and validate prediction models for exacerbation frequency, time to first exacerbation, and lung function decline.

Participants will visit the Clinical Research Centre at least once for sampling and clinical data collection, with consent obtained to link their samples to the C-BRIDGE database.

Ethics Approval:

Approved by the Ethics Committee of Shanghai Pulmonary Hospital and other participating centers.

Expected Outcomes:

The C-BRIDGE Study will establish detailed molecular endotypes of bronchiectasis in Chinese patients, facilitating precise prognosis prediction and tailored treatment strategies. By identifying and validating patient subgroups and biomarkers, it will provide a foundation for personalized medicine in bronchiectasis management, with potential relevance in China and worldwide.

Первичные конечные точки

• Frequency of bronchiectasis exacerbations [Срок оценки: 2 years]

Вторичные конечные точки (10)

• Time to the first exacerbation [Срок оценки: 2 years]
• The Quality of Life Bronchiectasis Respiratory Symptom Scales (QOL-B-RSS) [Срок оценки: 2 years]
• The Bronchiectasis Health Questionnaire (BHQ) [Срок оценки: 2 years]
• The Bronchiectasis Impact Measure (BIM) [Срок оценки: 2 years]
• The St Georges Respiratory Questionnaire (SGRQ) [Срок оценки: 2 years]
• The bronchiectasis exacerbation and symptom tool (BEST) [Срок оценки: 2 years]
• Bronchiectasis Symptom VAS (BS-VAS) [Срок оценки: 2 years]
• Forced expiratory volume in 1 second (FEV1) [Срок оценки: 2 years]
• Hospitalization for severe exacerbations [Срок оценки: 2 years]
• All cause mortality [Срок оценки: 3 years]

Критерии участия

Критерии включения

• A prior CT scan confirming bronchiectasis, accompanied by a compatible clinical syndrome including cough, sputum production, and/or recurrent respiratory tract infections.
• At the screening visit, participants must have been clinically stable for 4 weeks, defined as no antibiotic or corticosteroid treatment for a pulmonary exacerbation in the preceding 4 weeks.

Критерии исключения

• Inability to provide informed consent
• Age under 18 years
• Patients with active tuberculosis
• Use of antibiotics or corticosteroids for a pulmonary exacerbation within the past 4 weeks

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Китай · 9 центров

• Lin Liu — Guiyang
• Lei Song — Changchun
• Qian Qi — Цзинань
• He-feng Chen — Шанхай
• Zhou-fang Mei — Шанхай
• Jun She — Шанхай
• Xue-ling Wu — Шанхай
• Yong-hua Gao — Шанхай
• … и ещё 1 центр

Публикации

• Gao Y, Richardson H, Dicker AJ, Barton A, Kuzmanova E, Shteinberg M, Perea L, Goeminne PC, Cant E, Hennayake C, Pollock J, Abo Leyah H, Choi H, Polverino E, Blasi F, Welte T, Aliberti S, Long M, Shoemark A, Sibila O, Huang JTJ, Chalmers JD. Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study. Am J Respir Crit Care Med. 2024 Jul 1;210(1):77-86. doi: 10.1164/rccm.202310-1729OC PMID 38717347
• Choi H, Ryu S, Keir HR, Giam YH, Dicker AJ, Perea L, Richardson H, Huang JTJ, Cant E, Blasi F, Pollock J, Shteinberg M, Finch S, Aliberti S, Sibila O, Shoemark A, Chalmers JD. Inflammatory Molecular Endotypes in Bronchiectasis: A European Multicenter Cohort Study. Am J Respir Crit Care Med. 2023 Dec 1;208(11):1166-1176. doi: 10.1164/rccm.202303-0499OC. PMID 37769155
• Shoemark A, Shteinberg M, De Soyza A, Haworth CS, Richardson H, Gao Y, Perea L, Dicker AJ, Goeminne PC, Cant E, Polverino E, Altenburg J, Keir HR, Loebinger MR, Blasi F, Welte T, Sibila O, Aliberti S, Chalmers JD. Characterization of Eosinophilic Bronchiectasis: A European Multicohort Study. Am J Respir Crit Care Med. 2022 Apr 15;205(8):894-902. doi: 10.1164/rccm.202108-1889OC. PMID 35050830
• Chalmers JD, Aliberti S, Filonenko A, Shteinberg M, Goeminne PC, Hill AT, Fardon TC, Obradovic D, Gerlinger C, Sotgiu G, Operschall E, Rutherford RM, Dimakou K, Polverino E, De Soyza A, McDonnell MJ. Characterization of the "Frequent Exacerbator Phenotype" in Bronchiectasis. Am J Respir Crit Care Med. 2018 Jun 1;197(11):1410-1420. doi: 10.1164/rccm.201711-2202OC. PMID 29357265
• Huang JT, Cant E, Keir HR, Barton AK, Kuzmanova E, Shuttleworth M, Pollock J, Finch S, Polverino E, Bottier M, Dicker AJ, Shoemark A, Chalmers JD. Endotyping Chronic Obstructive Pulmonary Disease, Bronchiectasis, and the "Chronic Obstructive Pulmonary Disease-Bronchiectasis Association". Am J Respir Crit Care Med. 2022 Aug 15;206(4):417-426. doi: 10.1164/rccm.202108-1943OC. PMID 35436182
• Shoemark A, Griffin H, Wheway G, Hogg C, Lucas JS; Genomics England Research Consortium; Camps C, Taylor J, Carroll M, Loebinger MR, Chalmers JD, Morris-Rosendahl D, Mitchison HM, De Soyza A; Genomics England Research Consortium:; Brown D, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard PMID 35728977
• Hill AT, Haworth CS, Aliberti S, Barker A, Blasi F, Boersma W, Chalmers JD, De Soyza A, Dimakou K, Elborn JS, Feldman C, Flume P, Goeminne PC, Loebinger MR, Menendez R, Morgan L, Murris M, Polverino E, Quittner A, Ringshausen FC, Tino G, Torres A, Vendrell M, Welte T, Wilson R, Wong C, O'Donnell A, Aksamit T; EMBARC/BRR definitions working group. Pulmonary exacerbation in adults with bronchiectasi PMID 28596426
• Aliberti S, Lonni S, Dore S, McDonnell MJ, Goeminne PC, Dimakou K, Fardon TC, Rutherford R, Pesci A, Restrepo MI, Sotgiu G, Chalmers JD. Clinical phenotypes in adult patients with bronchiectasis. Eur Respir J. 2016 Apr;47(4):1113-22. doi: 10.1183/13993003.01899-2015. Epub 2016 Feb 4. PMID 26846833

Идентификаторы

NCT: NCT06900062 · 2024ZD0529700

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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