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      Endotype-driven prediction of acute exacerbations in chronic obstructive pulmonary disease (EndAECOPD): protocol for a prospective cohort study

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          Abstract

          Introduction

          Current strategies for the prevention of acute exacerbations in chronic obstructive pulmonary disease (COPD) are primarily based on clinical measurements but fail to target the pathophysiological mechanisms, namely endotypes, of the disease. Studies identifying endotypes underlying exacerbation susceptibility and discovering specific biomarkers may lead to the development of targeted therapeutics but are lacking. This study aims to assess a broad spectrum of biomarkers at multiple biological levels (genetics, airway inflammation and respiratory microbiome) for their ability in predicting acute exacerbations of COPD, thus enables high-resolution disease endotyping and may lead to precision treatment of the disease.

          Methods and analysis

          In this prospective cohort study, participants with stable COPD (n=600) will be recruited and assessed for demographics, symptom scores, spirometry, medication use and comorbidities at baseline. Blood will be obtained for genotyping variants in a panel of nine genes. Induced sputum will be collected for the profile of microbiota using 16S rRNA gene sequencing, quantification of bacterial load, inflammatory mediators assay and sputum cytometry. Participants will be followed up for their exacerbations till 12 months and reassessed for the clinical measurements as baseline. The primary outcomes are total number of exacerbations, severe exacerbations, moderate exacerbations and time to first exacerbation. The secondary outcomes are changes in lung function and symptom scores. The effect of biomarkers representing genetic variants, airway inflammation and respiratory microbiome on predicting the frequent exacerbator phenotype and exacerbation frequency will be analysed with multivariable modelling, and time to first exacerbation with a Cox regression model.

          Ethics and dissemination

          The study has been approved by the Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University (No. 2018–298). The results of the study will be published on peer-reviewed journals.

          Trial registration number

          ChiCTR1800019063.

          Related collections

          Most cited references29

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          John R. Hurst, Jørgen Vestbo, Antonio Anzueto … (2010)
          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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            New insights into the immunology of chronic obstructive pulmonary disease.

            Guy Brusselle, Guy F. Joos, Ken R. Bracke (2011)
            Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Lung microbiome dynamics in COPD exacerbations.

              Zhang Wang, Mona Bafadhel, Koirobi Haldar … (2016)
              Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.
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                Author and article information

                Journal
                Journal ID (nlm-ta): BMJ Open
                Journal ID (iso-abbrev): BMJ Open
                Journal ID (hwp): bmjopen
                Journal ID (publisher-id): bmjopen
                Title: BMJ Open
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2044-6055
                Publication date Collection: 2019
                Publication date (Electronic): 4 November 2019
                Volume: 9
                Issue: 11
                Electronic Location Identifier: e034592
                Affiliations
                [1] departmentDepartment of Integrated Traditional Chinese and Western Medicine , Sichuan University West China Hospital , Chengdu, China
                Author notes
                [Correspondence to ] Juan-juan Fu; fu.juanjuan@ 123456scu.edu.cn
                Author information
                http://orcid.org/0000-0003-3170-8629
                Article
                Publisher ID: bmjopen-2019-034592
                DOI: 10.1136/bmjopen-2019-034592
                PMC ID: 6858242
                PubMed ID: 31690612
                SO-VID: 798a2aaf-7261-47fb-888c-d5baacf8bee3
                Copyright © © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 14 June 2019
                Date accepted : 15 October 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No.81870014
                Funded by: Thousand Talents Program, Sichuan province, China;
                Award ID: No.0082204151045
                Categories
                Subject: Respiratory Medicine
                Subject: Protocol
                Subject: 1506
                Subject: 1731
                Custom metadata
                special-feature unlocked

                ScienceOpen disciplines: Medicine
                Keywords: chronic obstructive pulmonary disease,exacerbations,genetic variants,16s rrna gene analysis,respiratory microbiome,airway inflammation
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: chronic obstructive pulmonary disease, exacerbations, genetic variants, 16s rrna gene analysis, respiratory microbiome, airway inflammation

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