Transforming clinical research and science in bronchiectasis: EMBARC3, a European Respiratory Society Clinical Research Collaboration

James D. Chalmers, Stefano Aliberti, Josje Altenburg, Francesco Blasi, Clare Clarke, Sanjay H. Chotirmall, Megan L. Crichton, Raja Dhar, Pieter Goeminne, Charles Haworth, Michael R. Loebinger, Natalie Lorent, Eva Polverino, Felix C. Ringshausen, Amelia Shoemark, Michal Shteinberg, Oriol Sibila, Arietta Spinou, Tobias Welte
European Respiratory Journal 2023 61: 2300769; DOI: 10.1183/13993003.00769-2023

Tweetable abstract

EMBARC3 is a programme of clinical and translational research aiming to improve our understanding of bronchiectasis globally https://bit.ly/42n3HD8

Background

Bronchiectasis is a major health problem that is increasing in prevalence and burden globally [1, 2]. The impact of bronchiectasis on patients and the healthcare system is exacerbated by the decades in which the disease was under-recognised, under-researched and poorly treated [3]. There remain no treatments licensed by regulatory authorities worldwide, and many of the treatments that are used in routine clinical practice lack robust evidence [4]. Therapeutic development in bronchiectasis is undermined by the lack of experimental models and a lack of fundamental understanding of the disease. This makes bronchiectasis less attractive for investment into new therapeutic research compared to other fields.

However, bronchiectasis is now viewed as major success story in terms of bringing a disease from the shadows into the spotlight and stimulating a “renaissance” in disease awareness and understanding [5, 6]. In 2012, the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) was established as among the first European Respiratory Society (ERS) Clinical Research Collaborations, an ERS research scheme that now supports multiple areas of respiratory medicine (https://www.ersnet.org/science-and-research/ongoing-clinical-research-collaborations) [7, 8]. Over the past 10 years, EMBARC, along with researchers and global partners, has helped to develop the field of bronchiectasis into one of the most dynamic in the respiratory speciality. From 2022 to 2025 the EMBARC Clinical Research Collaboration has been renewed for a third time and expanded. “EMBARC3” has the goal of transforming our understanding of bronchiectasis through clinical research, translational science and clinical trials. This editorial outlines the background, aims, objectives and vision of the ERS EMBARC3 project.

The EMBARC3 project is built on the infrastructure established during EMBARC1 and EMBARC2; specifically, EMBARC has established a multicentre European registry, partnered with global registries which share the EMBARC data collection fields, allowing federated analysis [3, 9, 10]. During EMBARC2, the registry was expanded to incorporate the BRIDGE study (Bronchiectasis Research Involving Databases, Genomics and Endotyping: NCT03791086), which has built an international bioresource linked to high quality clinical data to stimulate translational research. In parallel, researchers, including pharmaceutical industry partners, have been encouraged to share data and make datasets available for reuse to stimulate bronchiectasis research as part of a “data repository”. Major contributions from this effort include defining the key predictors of future exacerbations and mortality [11–13], identification of patient phenotypes [14] and the key role of Pseudomonas aeruginosa in outcomes [15–17]. Recently, EMBARC has published an analysis of 16 963 patients from 28 countries, the largest prospective study thus far reported in bronchiectasis [18]. This analysis revealed the deep heterogeneity of the disease across Europe. Key highlights include that 59% of bronchiectasis is classified as idiopathic or post-infective. Pseudomonas aeruginosa and Haemophilus influenzae were the most common pathogens, but with remarkable geographical variation. H. Influenzae was the most common pathogen in many Northern European countries but was uncommon in Southern Europe, where much higher rates of P. aeruginosa infection were identified. Striking differences in treatments between countries were observed, indicating no internationally accepted standard of care. We also identified worse outcomes with higher rates of exacerbation and hospitalisation in Eastern Europe [18]. This data highlights the need for further research into the underlying causes of bronchiectasis, the mechanisms leading to highly diverse microbiota in different countries, and better evidence-based treatments, and to drive improvements in care in countries where bronchiectasis remains an orphan disease [18].

Tackling these unanswered questions will require translational and mechanistic research. The work of EMBARC in this area includes the identification of inflammatory endotypes, particularly those defined by neutrophil extracellular traps and the presence of Th2 mediated inflammation, and is now having a major impact on the field [19–22]. New evidence generated on inhaled antibiotics, macrolides and mucoactive drugs are also informing clinical care [23–27]. The established global collaborative network has led to the definition of research priorities [28], a consensus definition of bronchiectasis exacerbation [29], criteria to define the overlap between bronchiectasis and COPD [30], and a definition of the disease and key topics such as chronic infection [31]. Advocacy has led to the establishment of the World Bronchiectasis Conference first held in Hannover in 2016 and which is now an annual event, and World Bronchiectasis Day held for the first time in 2022 [32]. Patients have been at the centre of all EMBARC activities in partnership with the European Lung Foundation (ELF).

EMBARC3 aims and objectives

EMBARC has therefore built important foundations by gathering large amounts of data, biosamples and a critical mass of researchers, patients and other stakeholders. The challenge now is to capitalise on that infrastructure to achieve patient benefit. EMBARC3 is organised into work packages, each with their own rationale and key objectives. These are summarised here and in figure 1.

FIGURE 1
FIGURE 1

EMBARC3 summary of key work packages and objectives. EMBARC: European Multicentre Bronchiectasis Audit and Research Collaboration; GECCO: Genetics Encoding Complexity Ciliopathies of Bronchiectasis; ELF: European Lung Foundation.

The European Bronchiectasis Registry and Biobank

While great progress has been achieved through international registries, simply describing clinical observations of patients is insufficient to achieve the breakthroughs that are needed. Therefore, a key focus of EMBARC3 will be expansion of the EMBARC-BRIDGE study, which incorporates sampling of blood, sputum, nasal swabs, urine and bacterial isolates, as well as additional biosampling in substudies. The aim is to enrol 1500 patients by 2025 with long-term follow-up. The next stage of disease understanding and therapeutic development in bronchiectasis will come from studying our patients in greater detail. This means using “hypothesis-free” approaches, such as genomics, transcriptomics, proteomics and metabolomics, as well as hypothesis-driven investigations, and engaging with translational scientists and linking state of the art biology with high quality clinical data. Expanding data collection and translational science beyond Europe is critical given the global heterogeneity of bronchiectasis and so studies will not be limited to Europe [33].

“Early bronchiectasis” and genetics

A major gap in our current research into bronchiectasis is that nearly all existing research, particularly in adults, focuses on patients with advanced disease. This limits our ability to understand and therefore to therapeutically target patients at an earlier stage of this disease where radiological and clinical bronchiectasis may be reversible, or where severe disease could be avoided.

We want to understand why bronchiectasis develops and characterise the role of inflammation, infection and impaired mucociliary clearance (the vicious vortex of bronchiectasis) in the early stages of the disease. The majority of patients with bronchiectasis are believed to either experience a pre-bronchiectasis state (described as persistent bacterial bronchitis where infection and inflammation are present without established bronchiectasis [34]) or have clear risk factors, such as genetic predisposition (primary ciliary dyskinesia (PCD)) or inflammatory conditions (asthma, allergic bronchopulmonary aspergillosis, rheumatoid arthritis).

We aim to understand more about how bronchiectasis develops through studying patients with early bronchiectasis and persistent bacterial bronchitis in adults, from both a clinical and biological point of view.

In addition, the aetiology of bronchiectasis remains unknown in the majority of cases, so called “idiopathic bronchiectasis” [35]. It is likely many such patients have unrecognised or a combination of multiple underlying risk factors. Studying how bronchiectasis develops may reveal new therapeutic targets. We will investigate this through the GECCO study (Genetics Encoding Complex Ciliopathies of Bronchiectasis), which aims to perform whole exome sequencing on over 1000 patients with bronchiectasis. Analysis of this dataset is initially focused on identifying unrecognised PCD in patients with bronchiectasis, based on recent observations that PCD is grossly underdiagnosed, with 12% of patients with unexplained bronchiectasis in the 100 000 genomes dataset having unrecognised PCD [36]. The genetic data generated will be an invaluable resource for the bronchiectasis community and we will subsequently explore other potential genetic contributors to disease. There is an important opportunity to integrate data generated from genomics with other omics technologies to identify genotype–phenotype relationships.

Clinical trials and development of new therapeutics

For the first time, EMBARC will be leading multicentre clinical trials of new therapeutics in investigator-led trials designed to generate new evidence and further disease understanding. The GREAT-2 trial will investigate a novel monoclonal antibody treatment against P. aeruginosa infection and will commence in 2023 (ISRCTN70034823). The COVID-19 pandemic has made trials more challenging but also shown that randomised trials can be streamlined into effective, lower cost, higher sample size pragmatic studies [37]. While initially starting with more conventional trials of single therapeutics, we recognise that many widely used treatments will never be subject to conventional phase 3 trials, but clinicians still need evidence. Our ultimate goal is therefore the development of a pragmatic trial platform for bronchiectasis therapeutics.

Inflammation in bronchiectasis

The development of anti-inflammatory therapies for bronchiectasis holds the promise of transforming the management of this condition, where treatment to date has been heavily focused on antibiotics [38]. EMBARC has played an important role in defining the heterogeneous nature of inflammation in bronchiectasis. Going forward, EMBARC has an important role to play in studying inflammation in bronchiectasis to inform the development of novel therapies and supporting results that are being obtained from randomised trials. Using biological samples from the BRIDGE study, and from previously conducted randomised trials and our biobank, we will considerably expand our study of neutrophilic and eosinophilic inflammation to understand the best biomarkers and therapeutic targets, and to understand how anti-inflammatory treatments may result in clinical benefits.

Infection in bronchiectasis: diagnostics, the microbiome and treatment

Nearly all studies into the role of infection in bronchiectasis utilise sputum culture. Culture of respiratory secretions have well-documented limitations, including a lack of sensitivity and its qualitative nature. The development of novel methods to diagnose and monitor infections is therefore a key priority for bronchiectasis. Study of the microbiome and its interactions is already changing our view of what causes exacerbations and disease severity from an infection point of view [39, 40]. The failure of antibiotics to consistently demonstrate clinical benefits, even in patients with well-defined infection, suggests a need to change our fundamental concepts [23].

Most studies have focused on bacteria, but the COVID-19 pandemic highlights the importance of also considering the impact of viruses in chronic lung diseases, and fungi are also an important consideration [41, 42]. As well as in clinical practice, sputum culture is also widely used as an endpoint in clinical trials of antimicrobials [43]. We propose that the development of molecular tests could make trials more feasible, cheaper and more reproducible.

In this work package we will use samples from the BRIDGE study and related datasets, including interventional cohorts, to increase our understanding of the bronchiectasis microbiome/metagenome as well as to use interventions (experimental medicine) to define the role of infection in disease pathogenesis. Integration of the microbiome data with data from other omics, such as metabolomics, may help to understand functional effects of microbiome changes on disease pathogenesis.

Patient engagement activities

EMBARC seeks to put the patient at the centre of everything that we do. The project is supported by a patient advisory group co-ordinated by the ELF. We conduct regular research into patients’ opinions and practices, which is used for patient-centred publications such as those on travelling and nontuberculous mycobacterial lung disease which have been recently published [44, 45].

The highly successful EMBARC/ELF patient conference was first held in 2021 and has now been replicated in multiple disease areas. This will become an annual event (https://europeanlunginfo.org/bronchiectasis/patient-conferences).

Overlap with COPD and asthma

Bronchiectasis is seen in 50% of patients with moderate to severe COPD and in a high proportion of patients with severe asthma [46]. Patients with COPD and asthma as a primary or secondary diagnosis are frequently excluded from bronchiectasis research studies and also from studies of patients with these airway diseases. The consequence of this is that we do not know the optimal management of this patient subgroup, and we do not know if evidence derived in bronchiectasis, COPD and asthma studies apply to the overlap group.

During EMBARC2, the airways disease overlap work package developed definitions and proposed inclusion criteria for studies examining overlapping conditions [30, 46]. In this work package we aim to perform a detailed study of at least 300 patients with bronchiectasis, bronchiectasis associated with COPD, bronchiectasis associated with asthma, and “pure” COPD/asthma. Using detailed phenotyping, including measurement of airway inflammation, airway microbiome characterisation, mucus assessment, sputum properties and additional biological measures in sputum, we will carry out the most detailed characterisation of these conditions performed to date.

Conclusion

EMBARC3 represents an expansion of a highly successful ERS Clinical Research Collaboration. Our research agenda highlights a series of key unanswered questions in bronchiectasis, including the role of inflammation, what happens during early disease, the role of unrecognised genetic defects in aetiology and how bronchiectasis interacts with other airway diseases. We encourage all bronchiectasis researchers globally to continue to work together to address these and other questions, and to transform the field of bronchiectasis.

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Supplementary Material

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Acknowledgement

We thank Celine Genton and Elise Heuvelin from the European Respiratory Society (Lausanne, Switzerland) for logistical support.

Footnotes

  • Conflict of interest: J.D. Chalmers reports grants or contracts from Grifols, consulting fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxosmithkline, Grifols, Insmed, Janssen, Novartis, Pfizer and Zambon, and leadership or fiduciary roles as Chair of European Respiratory Society (ERS) Bronchiectasis Guideline Task Force, Chief Editor of the European Respiratory Journal, and Chair of EMBARC Clinical Research Collaboration. S. Aliberti reports grants or contracts from Insmed, Chiesi and Fisher & Paykel (paid to institution), royalties or licenses with McGraw Hill, consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland, Zambon, AstraZeneca UK, AstraZeneca Pharmaceutical, CSL Behring, Grifols, Fondazione Charta, Boehringer Ingelheim, Chiesi Farmaceutici Spa, Zcube, Menarini, MSD Italia, Physioassist SAS and GlaxoSmithKline Spa, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GlaxoSmithKline Spa, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini, and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Limited and MSD Italia. J. Altenburg reports no conflicts of interest. F. Blasi reports grants or contracts from AstraZeneca, Chiesi, GSK and Insmed; consulting fees from GSK, Menarini and OM Pharma; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Chiesi, GSK, Grifols, Insmed, Menarini, Novartis, Ompharma, Pfizer, Sanofi, Vertex, Viatris and Zambon. C. Clarke reports no conflicts of interest. S.H. Chotirmall reports consultancy for Boehringer Ingelheim and Pneumogen, and payment or honoraria from AstraZeneca, Chiesi and Inovio. M.L. Crichton reports no conflicts of interest. R. Dhar reports grants or contracts from Cipla. P. Goeminne reports payment or honoraria for lectures, presentations or educational events from GSK, MSD and Chiesi. C. Haworth reports grants or contracts from the National Institute for Health and Care Research (paid to institution), consulting fees from 30 Technology, CSL Behring, Chiesi, Insmed, Janssen, LifeArc, Meiji, Mylan, Novartis, Pneumagen, Shionogi and Zambon, and payment or honoraria for lectures, presentations, speakers. bureaus, manuscript writing, or educational events from Zambon, Insmed, Chiesi and 30 Technology. M.R. Loebinger reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2 and Savara, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Insmed, and a role as the ERS Infection Group chair. N. Lorent reports speaker fees or consultancy for Insmed and GSK. E. Polverino reports grants or contracts from Grifols, consulting fees from Bayer, Zambon, Pfizer, Chiesi, Shire, Shionogi, Insmed, Moderna and Pfizer, payment for expert testimony from Chiesi, leadership or fiduciary roles on the ERS Task Force For Bronchiectasis Guidelines and as co-chair of EMBARC, and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Zambon. F.C. Ringshausen reports grants or contracts from German Center for Lung Research (DZL), German Center for Infection Research (EU and European Federation of Pharmaceutical Industries and Associations; EFPIA), iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm (paid to institution), consulting fees from Parion, Grifols, Zambon, Insmed and Helmholtz-Zentrum für Infektionsforschung, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from I!DE Werbeagentur, Interkongress, AstraZeneca, Insmed, Grifols, and Universitätsklinikum Frankfurt am Main, payment for expert testimony from Social Court Cologne (paid to institution), support for attending meetings or travel from German Kartagener Syndrome and PCD PAG, and Mukoviszidose, participation on a data safety monitoring board or advisory board for Insmed, Grifols and Shionogi, leadership or fiduciary role in other board, society, committee, or advocacy groups as Coordinator of the ERN-LUNG Bronchiectasis Core Network, Chair of the German Bronchiectasis Registry PROGNOSIS, Member of the Steering Committee of the European Bronchiectasis Registry EMBARC, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD PAG, Speaker of the Respiratory Infections and tuberculosis group of the German Respiratory Society (DGP), Speaker of the Cystic Fibrosis group of DGP, Prinicipal Investigator for DZL, Member of the Protocol Review Committee of the PCD-CTN, and Member of Physician Association of the German Cystic Fibrosis PAG, and fees for clinical trial participation (paid to institution) from AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon. A. Shoemark reports research grants from AstraZeneca. M. Shteinberg reports grants or contracts from GSK and Trudell pharma, consulting fees from AstraZeneca, Boehringer Ingelheim, Dexcel, Kamada, Synchrony Medical, Trumed and Zambon, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim and Kamada, support for attending meetings or travel from Boehringer Ingelheim, AstraZeneca and Kamada, participation on a data safety monitoring board or advisory board for Bonus Biotherapeutics, Boehringer Ingelheim and AstraZeneca, leadership or fiduciary role in other board, society, committee, or advocacy groups with Israeli Pulmonology Society, Israeli Society for Tuberculosis and Mycobacterial Diseases, EMBARC as unpaid management board member, and ERJ and Chest as unpaid editorial board member, and receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical International. O. Sibila reports no conflicts of interest. A. Spinou reports no conflicts of interest. T. Welte reports grants or contracts from German Ministry of Research and Education, and consulting fees from AstraZeneca, GSK and Insmed.

  • Support statement: EMBARC3 is funded by the European Respiratory Society through the EMBARC3 consortium (CRC-2013-06). EMBARC3 is supported by project partners Armata, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Grifols, Insmed, Janssen, Lifearc, and Zambon. Supported by the Innovative Medicines Initiative and The European Federation of Pharmaceutical Industries and Associations companies under the European Commission–funded Horizon 2020 Framework Program and by Inhaled Antibiotic for Bronchiectasis and Cystic Fibrosis (grant 115721). J.D. Chalmers is supported by the GlaxoSmithKline/Asthma and Lung UK Chair of Respiratory Research. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received May 7, 2023.
  • Accepted May 27, 2023.

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Transforming clinical research and science in bronchiectasis: EMBARC3, a European Respiratory Society Clinical Research Collaboration
James D. Chalmers, Stefano Aliberti, Josje Altenburg, Francesco Blasi, Clare Clarke, Sanjay H. Chotirmall, Megan L. Crichton, Raja Dhar, Pieter Goeminne, Charles Haworth, Michael R. Loebinger, Natalie Lorent, Eva Polverino, Felix C. Ringshausen, Amelia Shoemark, Michal Shteinberg, Oriol Sibila, Arietta Spinou, Tobias Welte
European Respiratory Journal Jun 2023, 61 (6) 2300769; DOI: 10.1183/13993003.00769-2023
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