MICA: BRONCH-UK a multicentre and multidisciplinary partnership grant tackling unmet needs in bronchiectasis

2.1 Unmet Clinical Need

Bronchiectasis (BE) is a progressive respiratory (lung) disease characterised by cough, mucus and severe, recurrent bacterial chest infections with high rates of ill health, time off work and marked reductions in health-related quality-of-life. In almost half of cases, the cause of bronchiectasis is unknown (idiopathic) and treatment in these patients remains "best guess" or symptom driven. Bronchiectasis presents a huge challenge to patients and doctors because no effective treatment is available. Both the world's first national guidelines (authored by coapplicants of this proposal) and Cochrane "best evidence" review of Bronchiectasis confirms this situation, reporting that small single-centre studies with ill-defined patient groups have hampered the few attempts to study clinical interventions /drug trials, rendering them of unproven use.

Previously the MRC sponsored UK trials in Bronchiectasis in the 1950s: Since then major developments have been sorely lacking. This partly reflects a feeling that BE is rare. However recent evidence is against this: In the UK and the US healthcare demands due to BE and mortality rates are increasing with 70,000+ hospital admissions in the UK 2011. Based on projections from US health insurance claims there are 100,000 US patients. We have limited UK data on how common this bronchiectasis is: Experts have however estimated 30-60,000 patients are affected in the UK but recent research suggests over 100,000 are affected.

Whilst the small case series reported so far demonstrate that "unknown cause" (idiopathic) and post-infectious bronchiectasis are the leading causes, bronchiectasis can also complicate common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) or immune problems e.g. Rheumatoid arthritis. Cystic Fibrosis is an inherited (genetic) form of bronchiectasis which like COPD associated bronchiectasis has different outcomes, microbiology and management needs from Bronchiectasis. Cystic fibrosis is rare (10,000 cases in the UK) yet has made significant gains through multicentre working and coordinating research.

To date no large studies of the genetic causes of idiopathic bronchiectasis have been conducted as this requires large numbers of patients beyond that a single centre can provide. There is currently no registry of well characterised patients with Bronchiectasis anywhere outside the US. The US national registry was commenced recently and has 1200 patients that differ to UK patients. There is an urgent need to build a large cohort of UK patients with Bronchiectasis in which large enough studies can be undertaken; adding in a biobank is a key additional strength.

Brief description of the Cohort and Partnership
The cohort will comprise 3500 symptomatic adult patients with a High Resolution CT scans demonstrating bronchiectasis. Patients will be characterised on the basis of clinical history, clinical examination and detailed investigations that are already part of routine clinical care with yearly reviews. A DNA biobank (from a blood sample) will be collected and will form a world's first in bronchiectasis providing a unique resource allowing future genetic studies to identify underlying genetic causes & new targets for treatment.

The partnership links 9 recruiting centres with established clinics & track records in Bronchiectasis research spread across the UK that have never had funding to work together. Additionally ground-breaking scientific partners with expertise in relevant areas will for the first time allow comprehensive mapping of the knowledge gaps. Future research will be able to use the strength of the assembled cohort; we can deliver a programme of clinical trials that address fundamental issues.

We will therefore tackle three major unmet needs 1) Lack of expertise in the area, 2) Lack of a clinical evidence base 3) Basic science- attracting skilled scientists to work in the area.

3.1 Technical summary ; Our methodology is to

1) Set up a world leading multi-disciplinary partnership, that addresses translational gaps through collective, but never before, assembled expertise.
2) Develop industry & academia pre-competitive space workshops to define consensus statements, new mechanistic studies/ grants and clinical trials.
3) Biobank DNA & serum from 3500 well characterised databased patients with CT proven BE.
4) Create a large database of well-characterised BE patients to facilitate translational research and clinical trials. Databasing will include multiple fields aligned to national standards of care and additional fields (developed from the US Bronchiectasis database allowing international comparisons). Tagging of records to Office of National Statistics and HES data will allow prognostic indices to be developed.
5) Three Partnership pilot projects will focus on important events that have important mechanistic or pathfinding potential and mandate multicentre & multi-disciplinary approaches:
i) A clinimetrics study of outcome measures in BE Identify and define/ validate clinical outcome measures & biomarkers in an intensive pilot study of 100 patients including lung function (spirometry, lung clearance index), quality of life (QOL-B), culture and quantitative counts with exploratory biomarkers in blood & sputum (as compared to sputum 16SRNA microbiome).
ii) A pilot randomised placebo controlled trial of Pseudomonas aeruginosa bacterial eradication in patients who develop their first infection. This is cross-cutting and studies both patient and bacterial factors involved in P. aeruginosa persistence (16S microbiome analysis & virulence marker expression and human exome sequencing) to help identify vaccine targets.
iii) Identify the prevalence of P. aeruginosa epidemic strains and compare their phenoytpe and genotypes to non-epidemic / BE adapted strains, linking to an international genome project for additional comparative power.

6.1 The potential for developing new treatments and management strategies using a Bronchiectasis patient cohort was recognised by as a key priority in a roadmap exercise. Assembling this cohort of biobanked patients was chosen as the highest priority for this partnership above all other possible collaborative studies reflecting its pluripotency (see also 4.1, 5.1 & Pathways to Impact file).

The Bronchiectasis Patient Cohort and Biobank will have immediate and long term benefits: It will

i) provide an opportunity for basic science researchers to study a ready assembled well characterised cohort / select particular phenotypes of interest.
ii) identify new targets for drug therapy in the first translational gap through basic science studies.
iii) enable meaningful intervention studies in both the academic and pharmaceutical industry field.
iv) provide information to patients and their families which will help them manage or prevent complications of Bronchiectasis.
v) it will directly shape future patient care through mapping of outcomes and mortality.
vi) inform Department of Health & NHS commissioners of treatment burdens and healthcare use.
vii) allow development of better clinical guidelines for clinicians.

Impact on the first translational gap

Two key drawbacks to tackling "first translational" evidence gaps in bronchiectasis are;
1) The lack of a basic science roadmap of discovery in the field.
2) A lack of a large well characterised cohort that is adequately powered.
These have collectively resulted in understandable barriers to grant awards and successful research in the field. To date, for example, the MRC has funded only 1 study in bronchiectasis in the last 15 years. The impact of the partnership will be to identify such a roadmap across a broad range of scientific disciplines and secondly provide the cohort that is phenotyped/ characterised enough and in sufficient numbers to remove such concerns.

Impact on patient care - development of clinical guidelines.

An accessible, clearly defined patient cohort would fulfil an unmet clinical need to evaluate and optimise current management strategies and provide evidence-based clinical guidelines. It would also be possible to assess disease progression and the impact of physiotherapy on this progression.

Impact on clinical research and trials.

The reasons for variation in progression and the factors that ultimately determine this in bronchiectasis remain unclear. This cohort will be utilised to explore genotype-phenotype correlations in more detail by analysing the physiological, environmental and genetic factors that may be relevant to disease expression. The proposed cohort would also provide sufficient power to assess the efficacy of potential disease-modifying drugs, or novel interventional therapies such as inhaled antibiotic therapy. Proposed joint workshops with academic clinicians, regulatory authorities are expected to improve trials design, feasibility and regulatory approvals. The number and type of studies will be limited by recruitment of the various subgroups of interest e.g. Pseudomonas infected or naïve. Based on projections we would expect to secure funding for and conduct least 3 major interventional studies and 6 observational/proof of principle studies during the 5-year period of funding. Studies are likely to be in the region of 3 months to 3 years duration.

Impact of 'added value'.

This cohort will underpin multiple new studies that would have previously been impossible. This will support the work of multiple scientific beneficiaries across genetics, microbiology, proteomics and immunology.
The recent establishment of a US national database presents a unique opportunity for the field to have truly comparable outcomes. The ability to make a real impact on the lives of patients with this progressive and disabling disease will develop best through a global perspective as afforded by such comparative data.