Clinical Research Office by 22MpP5

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									                                   Clinical Research Office
                    Sheffield Teaching Hospitals & University of Sheffield
                               Baseline Research Strategy Identification, May 2011


Introduction

The Joint STH/UoS Clinical Research Office is examining approaches to increasing Sheffield’s rate of
success in attracting research funding. As an initial step, we would like to establish the basic
structure of each Directorate’s approach to research, identifying the themes being pursued, the
researchers working in each area, and the projects that are supporting the strategy.

We should therefore be grateful if you would be kind enough to complete the table below, referring
where appropriate to the associated Excel list of projects that are on record as being conducted
during the last five years. To help establish a comprehensive view of your strategy please provide as
much information as possible.

Basic Information
Please provide basic information about this data-collection exercise
STH Directorate                    Respiratory Medicine
Completed By                       Professor Moira Whyte (Research Lead and Theme 3), Prof Ian Sabroe
                                   (Theme 1), Dr Robin Condliffe (Theme 2), Prof David Fishwick (Theme 4),
                                   Drs Edenborough/Wildman/Pirzada (Theme 5), Drs Bianchi/Hughes (Theme
                                   6)
Approved By
Date Completed                     11th July, 2011
Research Themes
Please identify each of the main areas in which your Directorate is actively conducting research
#     Theme name                    Basic Concept                       Stage                                     Key Investigators
                                                                        (Basic, Translational, Clinical, Health
                                                                        Services Research, Industry)
1     Airways Disease               Understanding how innate and        Basic, Translational, Clinical            I. Sabroe, R. Lawson, M.
                                    adaptive immunity might be          Industry                                  Whyte, J. Wild, S. Renshaw,
                                    targeted to improve outcomes in                                               S. Walmsley and
                                    asthma and COPD                                                               collaborations with
                                                                                                                  Professor David Dockrell in
                                                                                                                  Infectious Diseases
2     Pulmonary Vascular            Investigation of aetiology,         Basic, Translational, Clinical            D. Kiely, R. Condliffe, C.
                                    pathogenesis and treatment of       Industry                                  Elliot, A. Lawrie
                                    patients with pulmonary vascular                                              (Cardiovascular Sciences
                                    disease both primary and                                                      TUOS), J. Wild (Radiology,
                                    secondary                                                                     TUOS), I. Sabroe, M. Whyte
3     Interstitial Lung Diseases    Investigation of aetiology,         Basic, Translational, Clinical            M. Whyte, S. Bianchi, S.
                                    pathogenesis and treatment of       Industry                                  Renshaw, S. Walmsley
                                    interstitial lung disease

4     Occupational Lung             Investigation of aetiology,         Clinical                                  D. Fishwick, C. Barber, A.
      Disease                       pathogenesis and management                                                   Curran (HSL)
                                    of occupational lung disorders
5     Infection and Immunity        Investigation of host-pathogen      Basic, Translational, Clinical            M. Whyte, I. Sabroe, F.
                                    interactions in the lung, with      Industry                                  Edenborough, M. Wildman,
                                    application to bronchiectasis, CF                                             D. Dockrell, S. Renshaw, O.
                                    and airway disease                                                            Pirzada
6     Ventilation                   Clinical use of ventilatory         Clinical, Industry                        S. Bianchi, R. Hughes
                                    strategies in diseases including
                                    neuromuscular and cardiac
                                    diseases
Historical Research Strategy 2006-2011
For each theme, please describe your research strategy during the last five years. Identify the
conceptual direction, the detailed approach to progress and your targeted funding bodies (e.g. NIHR,
Portfolio Charities, Industry, etc.).
The Respiratory Research Executive has identified 6 research Themes. Themes 1-4 are well
established with ongoing programmes. Themes 5 and 6 are established, with studies both
completed and in progress, but are still in development.

1. Airways Disease
The airways inflammation theme is the flagship of basic and translational research in respiratory
medicine. A series of investigations have explored how infections and other immune activators
might cause airway inflammation in health and in disease, with research focused mainly around the
mechanisms by which infections exacerbate asthma and COPD. The Sheffield group has produced
internationally regarded science and has attracted major MRC and Wellcome funding for
translational research.
Prof Ian Sabroe (MRC Senior Clinical Fellow 2004-2009, the first MRC Senior Fellow in respiratory
disease for approx. 15 years) has conducted a series of studies exploring how inflammation is
established, modelling the airway in vitro. His more recent work is translating this by creating new
human models of inflammation (challenging human volunteers in vivo with inflammatory stimuli),
creating novel anti-inflammatory agents (SAPS, published 2008), and studying the biology of
respiratory viruses. His work is currently funded by major grants from the MRC and Wellcome Trust,
with other support from Asthma UK and Heart Research UK.
Prof Moira Whyte has driven the establishment of one of the most respected respiratory science
groups in the UK, recruiting Ian Sabroe, Stephen Renshaw, Sarah Walmsley, and establishing robust
collaborations with Infectious Diseases, particularly through Prof David Dockrell. Her work, including
major MRC funding held with Ian Sabroe, and supporting the Wellcome funding of Sarah Walmsley,
has focused on the biology of lung inflammation. The collaborations within the group have led to
important roles in a major MRC/ABPI COPD consortium.
Dr Stephen Renshaw, current MRC Senior Clinical Fellow, has established a unique basic science
model of inflammation in the zebrafish, and is currently actively collaborating with pharmaceutical
companies to use this to screen for novel anti-inflammatory therapies, as well as exploring basic
models of disease. He holds extensive MRC funding, and funding from the EU FP7 programme.
Dr Sarah Walmsley (Wellcome Intermediate Fellow) has produced outstanding work determining
how hypoxia, and a specific protein, PHD3, has contributed to the regulation of neutrophilic
inflammation. She is highly respected in the field of how hypoxia contributes to airway
inflammation, holding a prestigious Wellcome Fellowship, and co-supervising an MRC Clinical
Training Fellow (Dr Roger Thompson).
Prof David Dockrell (Infectious Diseases) is a key group collaborator, establishing numerous
programmes of research with all the principal investigators listed here. His work on host-pathogen
interactions in pneumococcal pneumonia is highly respected internationally, and his exceptional
expertise in pathogen biology has enabled and driven exciting strands of research determining how
infections modulate lung disease.
Dr Rod Lawson (Clinical Lead for COPD) has collaborated with Prof Jim Wild using MRI imaging to
study regional ventilation and perfusion in COPD, funded by GSK. He has also contributed patients
and expertise to a number of industry-funded clinical trials in COPD and has previously held HTA
funding for a large trial in pulmonary rehabilitation. A recent PhD student won a European
Respiratory Society prize for work on swallowing in COPD.
We have a major and extensive focus on airway inflammation, with significant expertise in
understanding how inflammation happens, how we control infections, and how these processes are
dysregulated to cause disease. Work through our participation in the MRC/ABPI COPD consortium
will explore how local inflammatory responses are dysregulated in disease. This study will entail
research bronchoscopies, skin inflammation models and blood sampling of patients and both
smoking and non-smoking controls.
We have also developed new ways of studying inflammation. We have created a new skin model
which allows inflammation to be explored in healthy volunteers. We are using our unique
experimental models of skin inflammation to study basic mechanisms of leukocyte recruitment to
and persistence at inflamed sites (HRUK Clinical Training Fellow) and aim to establish an
experimental programme involving LPS-mediated induction of airway inflammation. We plan to
study defects in alveolar macrophage function in other specific disease areas, including HIV (MRC
Clinical Training Fellow) and IPF (ACF in Respiratory Medicine). Funded by a Wellcome Clinician
Scientist Fellowship, we also study patients with rheumatoid arthritis since their joint fluid is a
source of large numbers of inflammatory cells. Further developments over the next 5 years will
include study of alveolar macrophages from patients with pneumonia.
In order to tackle the problems of airway inflammation, which underpin common diseases such as
asthma and COPD, we have assembled a team of translational clinicians to develop novel research
strategies targeting these processes. Aims and outputs are illustrated here: acute pneumonias are
associated with an increased risk of myocardial infarction (MI), which is likely to be underpinned by
actions of the cytokine IL-1. A translational approach led by cardiovascular sciences examined how
IL-1 contributes to heart damage after the heart attack. We are now exploring, using our human
models, the roles for IL-1 in human inflammation and whether we can predict who might be at risk
of heart attacks, particularly in patients with respiratory disease. In work funded by the Wellcome
Trust we are also developing new inhibitors of inflammation that we hope may be of benefit for
patients.

2. Pulmonary Arterial Hypertension
The Sheffield Pulmonary Vascular Disease Unit (SPVDU) is one of the largest units specialising in
pulmonary vascular disease in Europe, with a referral population in excess of 15 million. During the
last 5 years research has focussed on 4 main strands: 1. Detailed Clinical Phenotype and
Bioresource, 2. Pulmonary and Cardiac Functional Imaging, 3. Pre-clinical models and discovery
science, 4. Industry-sponsored clinical trials.
Strand 1: We have compiled the largest ever registry of incident cases of pulmonary hypertension
(PH) across the whole spectrum of the disease (ASPIRE – currently in submission). We have also
published on the management and outcomes of pregnancy in PH and together with strand 2 have
published on the diagnostic utility of both CT and MR in PH associated with systemic sclerosis. This
work has been supported by unrestricted grants from the pharmaceutical industry (Actelion), which
have funded 3 research fellows. During the last 2 years we have developed a large biorepository for
the collection of samples from incident, treatment-naive patients. This provides a unique resource
allowing us to look for changes in biomarkers or gene expression during disease progression and
determine the effect of treatment, in conjunction with Dr Allan Lawrie (MRC Career Development
Award Fellow -Strand 3). This biorepository has been funded by the NIHR Cardiovascular Biomedical
Research Unit. Strand 2 has involved work on the role of imaging, particularly MRI, in the
assessment of PH, in conjunction with the University Academic Unit of Radiology (Professor J Wild).
Research has focussed on the effects of PH on the right ventricle, pulmonary arterial flow, lung
perfusion, structural changes related to interstitial lung disease. We have published on the
diagnostic utility of both CT and MR in PH associated with systemic sclerosis. A novel assessment of
oxygen uptake and V/Q matching in CTEPH using hyperpolarised Helium-MRI has begun. This work
has been taken forward with the help of two BMedSci students (Dan Hagger, Adam Telfer) and two
radiology research fellows (Andy Swift PhD, Smitha Rajaram MD), jointly supervised by David Kiely
and Jim Wild, and a part funded MRI-physicist (Helen Marshall). As well as the afore-mentioned
papers in the radiological assessment of systemic sclerosis-associated PH several papers are
currently in submission looking at novel cardiac parameters and novel ways of assessing parenchyma
and PE using MR. This work has also been funded by the pharmaceutical industry (Bayer and Pfizer),
with additional funding from the CV BRU and EPSRC. Strand 4: During the last 5 years we have
recruited patients to several multi-centre large randomised controlled trials including IMPRES –
imatininb, FREEDOM C – oral treprostinil, COMPASS – oral combination therapy, VISION –
combination oral/nebulised therapy, PATENT – riociguat, AMBITION – oral combination therapy.
Collaborations across divisions with clinicians and cardiovascular scientists are also helping to
develop new targets that might be important in the treatment of pulmonary hypertension. In
particular, we are examining the roles of hormonal systems that control fluid balance and blood
pressure in the development of pulmonary hypertension. We are also a leading contributor to early
phase clinical and experimental medicine trials in PH, and aim to phenotype and study our large
patient cohort to directly improve patient care over the next 5 years.

3. Interstitial Lung Disease
We have developed a regional referral service for ILD, underpinned by a specialist MDT meeting, and
have co-written the international guidelines for patient management (Thorax 2008). We are
participating in 2 major MRC funded studies (Whyte co-app), the Trent Lung Fibrosis Network and
the PROFILE Biomarker Study. Whyte is also a member of the UK Lung Fibrosis Network. We have
also contributed patients for industry studies, with 2 further studies planned. We have a relevant
basic science project determining the interplay between lung inflammation and fibrosis (funded by
Wellcome Trust) that has identified a potential therapeutic target in IPF, a disease with no effective
therapy and a very poor prognosis. Much of the basic science described in Theme 1 is also relevant
to this Theme.

4. Occupational Lung Disease
The occupational respiratory disease research theme is embedded within the Centre of Workplace
Health (CWH), a tripartite relationship between the Health and Safety Laboratory, the University of
Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust. The Centre has three strands of
activity; (i) research into occupational respiratory disorders, (ii) provision of “strategic” occupational
health services (such as occupational health needs assessments for industries) and (iii) teaching and
training issues. CWH has funded a number of clinical research fellows, 2 currently completing higher
degrees (Darby, Burton) and a further post currently advertised.

HSE generic research issues, 5 years of strategy; this has largely been driven by the requirements of
the major research funder in occupational respiratory ill health, the Health and Safety Executive
(HSE). Indeed, the direction of research into occupational respiratory disorders was driven early on
in this time period by government targets to reduce the incidence of occupational asthma
specifically. In this regard, our research strategy was to engage with HSE to formulate studies and
research ideas that would lead to a reduction in occupational asthma. Examples of such work include
the routes of referral study, diagnostic agreement of occupational asthma and the development of a
BTS standard of care for occupational asthma.

HSE specific issues; certain focused requirements have also been researched, and include case
definitions for occupational extrinsic allergic alveolitis, a large population study of COPD has been
carried out to better define the size of the population attributable fraction for COPD of relating to
harmful inhaled workplace exposures. Additional work has taken place to assess health surveillance
approaches, including the development of a position paper on beryllium-exposed workers.

Clinical issues; whilst the Centre for Workplace Health only has currently a limited capability to carry
out clinical research, as no job planned time is set aside for such work at consultant level, there is a
study currently running that relates to the use of exhaled nitric oxide in the assessment of patients
being assessed for possible occupational asthma.

The primary target for respiratory research monies is HSE. Other providers will be targeted as
required, although further work with BOHRF is anticipated. NIHR portfolio status is not granted to
HSE funded studies currently.

5. Infection and Immunity

Sheffield hosts the regional centre for cystic fibrosis (F. Edenborough, M. Wildman) and there is also
a specialist service in bronchiectasis and lung infection (O. Pirzada, S. Bianchi). A number of industry-
funded studies are underway or have been completed. Dr Wildman is a member of the UK CF
Registry Steering group and is currently working with this group to develop case mix adjustment
measures for the national registry. He has also carried out some epidemiological comparisons of US
and UK CF data using routine data. There is ongoing work within the CF unit to investigate objective
measures of adherence and this is linked with work to classify patients by stage of change in regard
to adherence behaviours. There are several, active clinical studies recruiting within STH and offering
patients further therapy for Bronchiectasis. Both portfolio and non-portfolio research work is
included with new anti-inflammatory studies planned to start this year. STH is collaborating with
other centres at an exciting time for Bronchiectasis and lung inflammation, working with several
other centres in the newly formed Northern Bronchiectasis Research group to help co-ordinate local
and multicentre- bronchiectasis related research. Much of the basic science described in Theme 1 is
relevant to lung infection and applicable in this area.

6. Ventilation

The Sheffield Thoracic Assisted Respiration and Sleep Service is operated by Drs Bianchi and Hughes.
It offers specialist management of conditions such as obstructive sleep apnoea and has a regional
commitment to the management of patients with chronic respiratory failure. Dr Hughes specialises
in the acute and chronic management of respiratory failure secondary to COPD while Dr Bianchi has
developed a service in non-invasive ventilation focussing on chronic respiratory failure secondary to
thoracic cage deformity, diaphragmatic weakness and neuromuscular disease. Several areas of
research have been developed focussing on the management of patients with chronic
neuromuscular weakness (particularly motor neurone disease), in patients with central sleep apnoea
related to cardiac failure and assessing the physical, neurocognitive and microvascular effects and
consequences of OSA and the therapeutic effects of CPAP.

Additional Information

Although not recorded as Respiratory Research Activity it should be noted that the Lung Cancer
service, led by Dr Jennifer Hill, recruits large numbers of patients to lung cancer trials based in
Weston Park. Indeed, Sheffield is one of the top recruiting centres in the national lung cancer
network.

We have a major and increasing emphasis on experimental medicine research directly studying the
human. We have two principal core experimental medicine themes within respiratory medicine,
pulmonary inflammation and pulmonary hypertension. We undertake internationally recognized
research into airway inflammation, neutrophil and macrophage biology and host pathogen
interactions. This work has been supported by 2 MRC and 1 Wellcome Senior Clinical Fellowship and
we have substantial current MRC funding. We have recently become a lead centre in the MRC/ABPI
COPD Consortium, a £7M initiative across 10 centres.

Research Strategy 2011-2016
For each theme, please describe your research strategy for the forthcoming five years, again
indicating direction, detail and funders.
1. Airways Disease

The theme has extensive strengths, but is facing significant challenges, with the changes to research
funding underway nationally. The strengths of the theme lie in its world-class research on
mechanisms of host-pathogen interactions in the airways. The theme will clearly continue to drive
the highest possible quality research in this area. Key targets will be the ongoing development of
translational themes (such as Prof Sabroe’s human challenge model), as well as developing the
translational research opportunities arising from the MRC/ABPI COPD Consortium, a key national
initiative bringing significant funding. The aims of the Theme will be to uncover how pathogens
cause inflammation of the airways, develop new targets that might be feasible treatment points for
airways inflammation, and develop research on existing targets and new therapeutics already
underway in the group. This work will enhance partnerships with Pharma (several discussions re
add-on studies to the MRC/ABPI initiative are underway).
Dr Sarah Walmsley will be supported for an application for a Senior Clinical Fellowship (Wellcome or
MRC), for which she should be very competitive.
Ongoing strategic thought is needed to maximise the research opportunities of the senior clinical
team. Prof Sabroe has moved from a 80:20 research:clinical commitment to a 50:50 job plan, which
reduces his maximum feasible input into strategic research. He is likely to apply for a Wellcome
Senior Investigator Award or ERC Advanced Fellowship, and will require significant support to write
these applications. Dr Renshaw will complete his Senior Fellowship in 2013, and if his substantial
expertise is to be retained, a suitable post will need to be constructed enabling support of his
ongoing research.
Dr Lawson/Pro Wild will continue to develop MRI imaging applications for COPD, e.g. in monitoring
treatment responses and as an intermediate phenotype of disease progression (advanced industry
interest in funding this area). Dr Lawson will also pursue further funding to investigate the role of
inspiratory muscle training in COPD. He has a number of clinical studies ongoing/due to start
(Boehringer Ingelheim/Pfizer).

2. Pulmonary Vascular Disease.

Strand 1 Detailed Clinical Phenotype and Bioresource: Continued expansion of the biorepository,
with additional funding being sought post BRU. Formation of a tissue biobank – a unique endeavour
to obtain post-mortem tissue from patients (Prof Sabroe). Ethics approval has been granted. Initial
pilot funding may be available from CVBRU funds with a view to obtaining longer-term funding from
a larger funding body. Our next research fellow will focus on systemic sclerosis-associated PH and
this work will involve both strand 2 and 3. They will focus on different groups of patients with
systemic sclerosis (PH +/-, ILD +/-. TLCO preserved or reduced) and will assess the use of novel
radiological parameters (hyperpolarised Helium and Xenon, perfusion time to peak) as well as
genomics in tightly phenotyped patients from each of these groups (funding – hopefully industry for
initial funding of fellow with view to a grant proposal (Arthritis Research UK)). We are also planning
to start recruitment later this year into a portfolio study of intravenous iron in idiopathic pulmonary
arterial hypertension (PAH) in conjunction with Hammersmith and Papworth (BHF grant and CLRN
funds). A further collaborative RCT (with Hammersmith hospital) of a novel agent (DCA) is also
planned. Strand 2 Pulmonary and Cardiac Functional Imaging: Our present 2 MD students will
complete their studies into novel MR parameters of pulmonary vascular function and disease. A pre
and post therapy study is planned for late 2011. An MRI investigation into the RH and LH interaction
in LH PH is planned for 2011 led by Andy Swift with Cardiology (Dr. Alli Morton). To fully investigate
MR as an evaluation of therapy in PH a large two centre NIHR HTA or EME proposal is planned which
will be led by Sheffield in collaboration with Papworth. A study of hyperpolarised 129Xe MRI as a
probe of interstitial thickening and gas transfer in systemic sclerosis associated PH is planned for late
2011-2012. In conjunction with Professor Rod Hose (Medical Physics) we plan to use of anatomical
and physiological sensitive measures from MRI and clinical tests as the basis for boundary conditions
and validation endpoints in multi-scale models of the pulmonary venous system and for patient
specific geometry. Funding for an EPSRC PhD student co-supervised by Wild and Hose has been
secured to take this image based modelling forward and it is planned to apply for European or EPSRC
funding for this collaboration. Strand 3 Pre-clinical models and discovery science: Work on novel
pathways TRAIL, OPG and IL-1 in PH will continue (Dr Lawrie) and it is hoped that phase 1 and 2
studies targeting this pathways will result (funding- MRC). Drawing on the expertise in inflammation
of Professor Sabroe, Professor Whyte and Dr Walmsley the role of HIF pathways and neutrophil
function in PH and especially the interaction with iron metabolism will be explored. Strand 4
Industry-sponsored clinical trials: Enrolment into current active studies will continue (PATENT,
AMBITION, COMPASS) while patients will continue to be followed in extension arms of completed
RCTs (FREEDOM, Tadalafil).
3. Interstitial Lung Disease

1. Continue recruiting to the MRC-funded portfolio-adopted studies, whilst preparing future grant
applications based on preliminary biomarker studies – Whyte/Bianchi

2. Explore translational potential of basic science findings with regard to the TRAIL death ligand to a
“first in man” study - Whyte

3. Develop novel MRI imaging techniques (3He and 129Xe) to explore V/Q mismatching in ILD,
together with novel applications for assessment of regional lung hypoxia Wild/Whyte/Walmsley,
building to a Clinical Fellowship application (Zhe Hoo, ACF in Respiratory Medicine)

4. Play a significant role in UK Lung Fibrosis Network applications to NIHR/MRC for multi-centre
studies

4. Occupational Lung Disease

Current national research strategy into occupational lung disorders is being formulated and
discussed by the GORDS group, the Group of Occupational Respiratory Disease Specialists. CWH will
play a part in formulating this strategy.

HSE generic issues; it is likely that our research strategy will align with HSE’s needs and also take into
any formulated GORDS view. The current priority research areas summarised by GORDS are as
follows;

Occupational COPD, causation and interventions

Occupational asthma interventions and redeployment

Occupational extrinsic allergic alveolitis

5. Infection and Immunity

Infection and Immunity will benefit from a prospective database that is planned within the
department. Drs Edenborough and Bianchi attend the Northern Bronchiectasis research group which
is performing a Delphi study to identify areas of research for collaboration across the region. The
portfolio of industry studies and collaboration with the Clinical Research Facility will continue to
expand. CF is currently undergoing a major service improvement project (led by M. Wildman) with
microsystems analysis in collaboration with the CF Trust, the North American CF Foundation and
Dartmouth University with grant applications in preparation. This unpacking and optimisation of the
clinical management of CF is determined to identify what elements of treatment matter to patients,
optimising adherence using motivational interviewing techniques and changing the service
infrastructure from being reactive (dealing with infection and weight loss) to prevention in a more
structured way including telemedicine, emonitoring and feedback from logging devices.

6. Ventilation

The research programme for sleep & ventilation, while in its infancy, is expanding through greater
involvement in national studies and through expansion of local projects. To date we have explored
the effect of CPAP therapy in moderate/severe OSA in terms of effect on exercise ability and are
nearing completion of a lifestyle intervention/motivational interviewing intervention study
capitalising in improvements in exercise ability. We plan to explore mechanisms of effect through
cross sectional studies and through analysis of blood biomarkers and changes in microvascular
function. We aim to expand these studies through a multicentre approach utilising telemedicine as a
modality of therapy delivery. Furthermore early studies have been conducted exploring the physical
and neurocognitive consequences of sleep deprivation in late pregnancy and secondary to sleep
apnoea. Dr Bianchi is collaborating with The University of Sheffield Psychology Department in
exploring consequences and beliefs regarding sleep deprivation in new mothers. The group are key
members of a national consortium proposing a large NIHR study (SAVE) exploring the effect of CPAP
therapy on cardiovascular outcomes in patients with cardiovascular and cerebrovascular disease
with previously undiagnosed or mildly symptomatic OSA. In patients with severe congestive cardiac
failure we are a recruiting site for the international SERVE-HF study exploring the use of
autoservoventilation in patients with consequent central sleep apnoea or Cheyne-Stokes
Respiration. Dr Bianchi is a co-investigator in a number of collaborative studies with the department
of neurology exploring aspects of care related to NIV in MND. A study exploring the role of cough-
assist devices for enhanced sputum clearance in patients commencing NIV is in progress, as is a
study exploring patient and carer experience of the NIV initiation and management process
following the development of respiratory failure. Furthermore, studies exploring mechanisms of
early detection of respiratory failure and validation studies of transcutaneous CO2 monitoring are
ongoing. The group are about to start recruitment to the NIHR funded DiPALS Trial, and multicentre
UK study of diaphragmatic pacing in MND patients with respiratory failure. Dr Hughes has developed
a research programme within the Respiratory Support Unit exploring the use of transcutaneous
carbon dioxide monitoring against arterial blood gas analysis (the currently accepted gold standard).

Specific Targets 2011-2012
Finally, for each theme, please identify in detail the specific targets you hope to meet during the next
12 months. Please indicate the projects you expect to develop, the funding bodies to which you will
be applying, and the projects and funding involved, naming the lead researcher in each case.
1. Airways Disease
1. Application to Wellcome Trust and MRC for a Senior Clinical Fellowship (Sarah Walmsley)
2. Application to continue the MRC/ABPI COPD consortium, with additional industry applications
(Whyte/Dockrell/Sabroe).
3. Successful publications of key studies of new human models of inflammation (Sabroe), recently
funded for further development by Heart Research UK.
4. Exploitation of novel data in neutrophil biology to generate key publications (Sabroe/ Whyte) and
apply for further MRC funding
5. Completion of GSK-funded MRI imaging study in COPD (Lawson/Wild)

2. Pulmonary Vascular Disease
Strand 1 Detailed Clinical Phenotype and Bioresource.
    i.      Biorepository (Kiely) – obtain funding (CVBRU/other) for continued sample collection
    ii.     Tissue Bank (Sabroe) – obtain pilot funding (CVBRU/other) and commence recruitment
    iii.    Clinical Research Fellow (Kiely) – obtain initial funding (industry) and commence post
            leading to grant proposal to Arthritis Research UK.
    iv.     Ferrinject study (Kiely) – commence recruitment (BHF/CLRN)
    v.      DCA study (Kiely) – commence recruitment
    vi.     Develop clinical trial of aldosterone antagonist (Sabroe/Condliffe) – funding stream tbc
Strand 2 Lung and Cardiac Functional Imaging.
    i.      Novel MR parameters (Wild/Kiely/Condliffe/Elliot/Swift) – Finish current work and
            several publications. Plan application to HTA for NIHR funding to help establish high
            throughput of PH and PE MRI research scans and fund future clinical fellows, MRI
            physicist and research radiographer.
    ii.     Hyperpolarised gas MRI (Wild/Elliot/Condliffe/Kiely) – Finish pilot 3He study and publish.
            Commence 129Xe study in SS PH (Wild/Kiely/Condliffe/Elliot).
    iii.    Computational modelling (Wild/Hose/Kiely/Clayton/Lawrie). Recruit PhD student
            physicist/mathematician. Use data for pilot for large image based modelling grant with
            potential preclinical imaging and modelling component.
Strand 3 Pre-clinical models and discovery science:
    i.      Develop clinical trial of IL-1 based therapy (Lawrie) – funding stream tbc
3. Interstitial Lung Disease
1. Significant recruitment to the MRC-funded Trent Lung Fibrosis and PROFILE studies -
Whyte/Bianchi

2. Explore possibility of a TRAIL “first in man” study - Whyte

3. Obtain ethics approval then pilot data for 3He/129Xe MRI imaging in ILD

4. Occupational Lung Disease
1. Further development of GORDS related research (David Fishwick, Chris Barber)

2. Further development of occupational COPD work in collaboration with Imperial College (David
Fishwick)

3. Further development of a standard of care with the BTS, for workers with COPD (David Fishwick)

4. Further development of metal working fluid alveolitis case definitions (Chris Barber)

5. Further development of silica and foundry work (Chris Barber and David Fishwick)

5. Infection and Immunity
1. CF microsystems analysis, Dr M Wildman; 1 year project , application to, specific goals
2. CF electronic patient record, Dr F Edenborough; collaboration with Leeds and EMIS, conversion to
full EPR using trend analysis tools and to feed into 1 above. No specific grant applications at this
stage but considerable overlap with funding strategies in 1 above.

6. Sleep & Ventilation
1. Complete BMedSci, MPhil and PhD student projects and submit papers for publication
2. Continue/commence recruitment to NIHR studies
3. Seek funding for microvascular studies and prepare telemedicine/multicentre protocols for ethical
clearance and funding applications (NIHR)

Infrastructure Requirements
To fulfil your ambitions you will be expecting to rely on the provision of central services and facilities.
To help with the planning of this provision, please identify for each of your themes your expectations
of the core facilities required to allow you to deliver your outputs. These might include laboratory,
imaging and pharmacy facilities, CRF availability, research nursing staff, advisory staff etc.
Timetabled quantification will be particularly helpful.
There are some important generic issues for Respiratory Medicine:
1. A general paucity of research support in Respiratory Medicine, in terms of dedicated research
nurses and admin/clerical support. We have been allocated 1 day per week of an excellent research
co-ordinator but clearing ISR/ethics/R&D hurdles is undoubtedly limiting our rate of progress.
2. Provision of sample storage/biobanking in the post-BRU era.
3. The current lack of any patient database to facilitate patient recruitment to studies.
4. The requirement for ongoing respiratory physiology and bronchoscopy on the RHH site. Many
specialist clinics are held at the RHH site with patients attending who may be suitable for research
(PH/ILD/COPD/Asthma/OLD).
5. Radiology support is critical for lung disease research. Specific issues with regard to MRI are
discussed below but CT scanning also essential.
6. We are dependent upon CRF support for our Portfolio-funded studies
7. Pharmacy support is essential for a number of the studies described.

Issues raised by Themes include:
Airways Disease
1. Reduced consultant time available for research as external Fellowships expire
2. Availability of research PET scanning could greatly enhance translation of novel observations

Pulmonary Vascular Disease
1. Research nurse support for continued recruitment of the PH Bioresource
2. CRF/Research nursing staff support for Ferrinject study (will be a Portfolio Study)
3. Assurance of patient throughput for clinical and research MRI scans and interaction with NHS
radiology management, upon which all of Strand 2 depends
4. Continuation of the tissue biorepository and sample storage facilities currently supported by the
BRUs

Interstitial Lung Disease
1. Lack of patient database for tracking of patients with rarer lung diseases
2. Concerns about imaging pipeline as above
3. Desirability of a biobank resource for some of these patient groups

Occupational Lung Disease
The core facilities within CWH are based at the Health and Safety Laboratory in Buxton. The latter is
an agency of HSE, and represents a state of the art laboratory facility. All research work
commissioned by HSE, with few exceptions, are carried out at this site. In order to maximise our
clinical research, the following core facilities would be a requirement;

1. Access to a respiratory physiology laboratory, with a specific and non-specific challenge facility;
this is currently present at RHH. Support from a part time respiratory physiologist would greatly
assist new study development (within 1 year)

2. Access to a searchable research style database to identify suitable research patients with
occupational respiratory diseases (within 1 year)

3. Access to a research database to allow inclusion of consenting NHS patients to be enrolled in
clinical research, and to allow assessment of group data (for example quality control studies, cohort
studies), (within 1 year).

4. Access to database expertise for epidemiological studies.
5. Access to immunology laboratory facilities that can assess simple and complex immunology
relevant to occupational sensitisation (IgE, IgG, flow cytometric facilities)

Sleep & Ventilation
Research within the sleep service has been, and remains, significantly compromised due to the high
clinical burden, lack of dedicated research staff and space/equipment. To date, therefore, studies
have been conducted by students undertaking brief research projects and have taken sole
ownership of the entire project reducing time burden on respiratory physiology staff. Attempts to
more closely involve physiologists have been confounded by clinical workload and cross-site working
to the extent that studies have failed to recruit. Alternatively, for larger studies, research staff from
the CRF have been utilised to good effect (but at substantial additional cost). Access to a research
database would additionally be of substantial benefit. Little time is available within consultants
working plans to deliver high quality research.

								
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