Matters was established 8 years ago with the aim of finding better treatments
for interstitial lung diseases (ILD) and lung infections. Since that time, we
have raised money and awareness into these often neglected conditions. Looking
back over the 8 years, we have come much further than any of us would have
anticipated in the beginning. We have established new theories on the
development of ILD or lung fibrosis and the role of the immune system in
particular the clotting cascade and neutrophils. We also have better ways of
monitoring and diagnosing these conditions and our novel nuclear medicine
imaging programme and relatively non-invasive lung biopsy service are the first
in the UK. We could not have achieved any of this without the support of our
funders and our patients, so thank you all. This review highlights our achievements
to date and our future directions in ILD.
Relatively Non-Invasive Lung Cryobiopsy (2014-ongoing):
Objective: To find a less invasive and better diagnostic tool for every patient with ILD
Main benefactors: Teresa Timberlake and family – equipment purchase + Lawrence Matz Memorial Fund – Clinical Fellow
Breathing Matters investment: £52,000 salary; £36,000 (total £88,000)
Leveraged funding: £347,000
cryobiopsy service, first in the UK including training other centres;
presentations at European Respiratory Society (2015), British Thoracic Society
(2014-6); publications: review 2016; papers in preparation:
Lung-INHALE study Study (2019) to assess inhaled drug deposition using
CLB. This will allow drug companies to
develop inhaled therapies for IPF and be sure that they are reaching the part
of the lung where they are needed. The use of inhaled therapy will avoid some
of the side-effects of anti-fibrotic drugs that are taken as tablets.
project was developed in discussion with a family whose mother had had a
surgical lung biopsy towards the end of her life. Her experience was such that
her family felt that a less invasive alternative must be available. Dr Theresia
Mikolasch, the Lawrence Matz Clinical Fellow, took this on for Breathing
Matters to find out about and train in new techniques. Dr Mikolasch then
returned to UCLH and established the first and only UK cryoscopic lung biopsy
(CLB) service. CLB is a new way of obtaining larger lung biopsies using a
flexible bronchoscope passed into the lungs through the mouth. The patient is
sedated and surgery is avoided. This is not only better for the patient than a surgical lung
biopsy, but also provides a solution to
the lack of biopsy samples available for scientific research. GSK were so excited by the technique that
they awarded Dr Mikolasch and Dr Porter a grant of over £300,000 to carry on
the service for an additional 3 years.
Novel FDG-PET Imaging
to Predict Prognosis and Response to Treatment in ILD (2014-ongoing):
Objective: To find a new test (biomarker) that will enable us to predict prognosis and response to treatment in each individual patient.
Breathing Matters investment: £34,766
Leveraged funding: £173,850
Funding from BLF for clinical trial of FDG-PET in post transplant bronchiolitis £40,000
Outcomes: Novel FDG-PET imaging
programme in ILD – first in the UK; presentations at American Nuclear Medicine
Society (2015), British Thoracic Society (2015-6); American Thoracic Society
Pulmonary 18F-FDG uptake helps
refine current risk stratification in idiopathic pulmonary fibrosis (IPF). Win
T, Screaton NJ, Porter JC, Ganeshan B, Maher TM, Fraioli F, Endozo R, Shortman
RI, Hurrell L, Holman BF, Thielemans K, Rashidnasab A, Hutton BF, Lukey PT,
Flynn A, Ell PJ, Groves AM. Eur J Nucl
Med Mol Imaging. 2018 May;45(5):806-815. doi: 10.1007/s00259-017-3917-8. Epub
2018 Jan 16.
Synergistic application of pulmonary 18F-FDG PET/HRCT and computer-based CT analysis with conventional severity measures to refine current risk stratification in idiopathic pulmonary fibrosis (IPF).
Fraioli F, Lyasheva M, Porter JC, Bomanji J, Shortman RI, Endozo R, Wan S, Bertoletti L, Machado M, Ganeshan B, Win T, GroveEur J Nucl Med Mol Imaging. 2019 Sep;46(10):2023-2031s AM.
will be used as a response biomarker to see if we can detect which patients
benefit from anti-fibrotic therapy and which patients do not benefit. We are
applying to the NIHR for a £400,000 grant to carry out this study:
others have shown that patients with IPF are more prone to blood clots. We have
some very exciting work looking at anticoagulation in IPF. We have completed 2/3rds of the study and
will then publish our findings later in 2020 (see below).
Interstitial lung disease (ILD) consists of a heterogeneous group of
diseases with varying amounts of interstitial inflammation and fibrosis.
Survival in the most severe form of lung fibrosis, idiopathic pulmonary
fibrosis or IPF, is particularly poor; however, there is heterogeneity in
outcome. Some patients gradually deteriorate; some undergo stepwise
progression, whilst others decline rapidly. Moreover, much of the prognostic
data heralds from an era when the criteria for diagnosing IPF were less well
and differently defined than at present.
There is a definite need to find prognostic biomarkers to predict
outcome in IPF patients
Positron emission tomography
(PET) offers the ability to non-invasively investigate cellular metabolism in
vivo. PET studies in animals have yielded valuable insights into the biology of
IPF and ILD and there is potentially encouraging evidence that PET may aid the
development of therapeutic interventions to treat these debilitating
conditions. It has been recently demonstrated that 18F-Fluorodeoxyglucose
(18F-FDG) PET signal is consistently raised and can be objectively measured in
patients with IPF. Moreover, these PET signals are shown to be stable and
We have shown over several
years and imaging hundreds of patients with ILD that the baseline measures of
pulmonary 18F-FDG PET signal to predict survival in patients with IPF compared
to other more established prognostic data.
We have also shown that combing PET data with our clinical scoring
system based on gender, age and physiology (GAP) data (“PET modified GAP
score”) refined the ability to predict mortality.
Future studies are to
investigate the role of FDG-PET scanning in other ILDs, such as Rheumatoid
arthritis (see below) and systemic sclerosis.
Arthritis (RA) Associated ILD (2018-ongoing):
Objective: To discover why 1:5 patients with RA will develop lung fibrosis and what novel treatment can prevent disease progression.
Breathing Matters investment: £34,766
Leveraged funding: £102,766
Outcomes: Novel biomarker test for neutrophils extracellular traps (NETS) in ILD in discussion with UCL business for further development; presentations at American College of Rheumatology (2014-6); British Thoracic Society (2016); British Rheumatology Society (2014-6);
The lung in a cohort of rheumatoid arthritis patients-an overview of different types of involvement and treatment. Duarte AC, Porter JC, Leandro MJ. Rheumatology (Oxford). 2019 Nov 1;58(11):2031-2038. doi: 10.1093/rheumatology/kez177.
Autoimmune rheumatic disease IgG has
differential effects upon neutrophil integrin activation that is modulated by
the endothelium. Khawaja AA, Pericleous C, Ripoll VM, Porter JC, Giles IP. Sci
Rep. 2019 Feb 4;9(1):1283. doi: 10.1038/s41598-018-37852-5.
Next steps: To work with a group in
Cold Spring Harbour, USA to see if inhibiting NET formation prevents
fibrosis. To see if the presence of NETs
in the blood can predict whether patients will develop lung fibrosis.
RA is a chronic debilitating disease estimated to afflict 13% of the
world population. Around 10% of patients with RA will develop an ILD that is
very similar to the lung fibrosis that we see with IPF. Dr Akif Khawaja was
funded by Rosetrees and UCL to carry out a PhD into the aetiology of RA-ILD.
His work proposed that RA is a disease that starts in the lung. That chronic
lung damage caused by smoking, infection and other insults causes the immune
response to recognize the lungs and joints as “foreign” and attack them causing
chronic damage. His work implicated neutrophils in this process and, in
particular, the p38 MAPkinase pathway.
We are hoping to develop a new test using blood or sputum to detect
early activation of neutrophils in the lungs of patients at risk of ILD. This same test may act as a biomarker for
prognosis and to detect early response to novel therapies.
Trial of Anticoagulation in IPF (2016-2020):
Objective: To assess the potential of anticoagulation as a treatment for IPF
Main benefactors: The Hulme Family – The Mark Hulme Clinical Fellow
Breathing Matters investment: £40,000
Leveraged funding: £100,000 from UCL/H NIHR BRC
Next steps: A trial of
anticoagulation with heparin in IPF using FDG-PET as a response biomarker
At present, we do not know the exact cause of idiopathic pulmonary
fibrosis (IPF), although research has identified lots of processes that are
likely to be involved. Currently, we believe that microscopic injury occurs in
patients with IPF and then the body responds to repair this, but does so in a
way that leads to more damage and scarring. One of the processes involved in
repair pathway is coagulation, which minimises blood loss when tissues are
damaged. Patients with IPF are at
increased risk of blood clots and this can reduce their already low life
expectancy. We also think that these blood clots drive the worsening of their
lung disease. Researchers have shown that clotting is over-activated in the
lungs of IPF patients and we want to investigate how reducing this might
improve the disease. Based on work
carried out at UCL, we believe that anticoagulation with heparin is safe and
may even prevent disease progression in IPF. Patients will be asked if they would
be willing to take the oral anticoagulant dabigitran for 3 weeks, to reduce
clotting. We will perform blood tests and FDG-PET scans before and after taking
the drug to judge response. If we find
that the heparin is safe and the patients report some improvement that we can
confirm with questionnaires lung function and FDG-PET scans, then we will
progress to leverage funding for a much bigger trial. We have completed 2/3rds of this study and have
analysed the results. We have found a small effect and the suggestion is that
we look in a few more patients that we will recruit early in the New Year.
Trial of a Novel Treatment (Compound X) in IPF (2019-2022):
Objective: To assess the potential of Compound X as a treatment for IPF
Main benefactors: NIHR BRC £100,000
Breathing Matters investment: £40,000
Leveraged funding: Application to British Thoracic Society, Wellcome Trust and NIHE.
Next steps: A trial of Compound X in
patients with IPF
Assessing effectiveness of treatments for IPF is difficult as often they
do not make patients feel better, despite decelerating disease. Currently, we
are guided by regular breathing tests and special imaging of the lungs, which are
insensitive to changes and may be unpleasant for patients. We need better tests
like a simple blood test to predict the prognosis for individual patients, and
their responses to treatment. Causes of IPF are unknown, but we have found that
specific white blood cells, called neutrophils, are increased in the lungs of
patients with IPF. We also found that the more neutrophils in the lungs, the
faster the decline from IPF. This suggests that neutrophils are actively worsening
IPF. Neutrophils produce a substance called X that we detect in the bloodstream
of patients with IPF. No-one has investigated whether X causes or worsens IPF. We
plan to quantify X in the blood and lungs of patients with IPF. By comparing X
levels in patients with IPF against healthy individuals, this will establish
whether X is increased in patients, whether high levels of X indicate more
severe IPF and whether treatment for IPF reduces X levels in patients that
respond. These results will ultimately help design future clinical trials
testing Compound X that is able to block X as a treatment for IPF.
Mucin 5 B and Its Role in IPF (2019-2022):
Objective: To assess the role of Muc5B in IPF
Main benefactors: NIHR £300,000
Breathing Matters investment: £40,000
Next steps: Further investigations
in patients with IPF of the effects of blocking neutrophil activation
Publications: A review on mucins in lung disease has been submitted and we hope this will be published in 2020.
It is unclear what causes IPF, but it is thought to be a response to
damage to the lining of the airways (epithelium) following an unidentified
injury. This results in the
formation of excessive scar tissue which disrupts the delicate
architecture of the lung and ultimately death follows from respiratory
failure. We have shown from research
previously sponsored by The Rosetrees Trust that a certain type of white blood
cell which is specialised in fighting infections called neutrophils may play a
role in PF. We have found that neutrophils are increased in the blood and lungs
of patients with PF and the more neutrophils you have, the worse the
individual’s outcome. In addition, it is
recognised that you are more likely to develop IPF if you have a commonly
occurring genetic mutation that causes increased mucus production by the lung
epithelium, and in particular a protein called Mucin or MUC5B that gives sputum
its stringy quality. We propose that the overproduction of MUC5B may stress the
epithelium, making it more prone to damage and scarring. In addition, the increased
MUC5B will attract and activate neutrophils from the blood and these white
blood cells can cause further damage. We hope that, by identifying treatments
that limit the number of neutrophils moving into the lung, we can protect
patients from developing PF or from PF progressing. We will use neutrophils and
epithelial samples form patients and healthy volunteers to compare differences
and see how the MUC5B affects neutrophil activation in the lung. Lastly, we
plan to block neutrophil activation and recruitment with a specific treatment that
is already being developed for other indications and has an excellent safety
profile. If our results are encouraging, we can take this medication into an
early clinical trial for patients with IPF.
We have also shown that we can detect very early changes in the CT scans
of patients that make too much Muc5B and this might be a very early sign, even
before the scan looks abnormal, that these patients are at risk of lung
If you are a UCLH
patient and want to get involved in any of the above studies, please discuss
this with your consultant.