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Autumn 2020 Newsletter – Out Now

 

For the Autumn 2020 newsletter, please click here

 

 

 

 

Can COVID-19 cause lung fibrosis?

The interstitial lung diseases (ILDs) are a group of over 200 different diseases that may result in lung inflammation or (in the worst case) pulmonary fibrosis (PF). There are many different aetiologies for ILD/PF and in some cases,  we do not know the cause, so called ‘idiopathic’. One of the questions that we at Breathing Matters want to answer is can COVID-19 give you pulmonary fibrosis? There are a few clues that this might be the case. Other coronaviruses such as Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS) have been reported to cause PF in a small percentage of patients, but of course the numbers of patients affected by SARS-CoV-2, the virus that causes COVID-19, will be much greater so, even if only a small percentage are affected, the numbers may still be very large. The diagnosis of ILD/PF is suggested by a clinical finding of breathlessness and abnormal lung function. The diagnosis is then confirmed with a CT scan of the chest.

Initial studies from China, Italy and the UK have remarkably similar findings. Of patients with COVID-19 discharged from a hospital in China, nearly half had abnormal lung function (Mo X, et al. European Respiratory Journal 55: 2001217, 2020).  Data from Leeds of patients with COVID-19 discharged from hospital showed that the majority (75% of those admitted to intensive care, and 65% of those admitted to the regular wards) still suffered from fatigue at 6 to 8 weeks post discharge. The number suffering from continual breathlessness was also high (70% of those admitted to intensive care, and 45% of those admitted to the ward).  (Halpin S et al. Journal Medical Virology, First published: 30 July 2020, DOI: (10.1002/jmv.26368).  An Italian study from Rome found that at 60 days around 55% of patients were suffering from fatigue and 40% from breathlessness.  It is unclear what is the cause of these high levels of breathlessness, but a study from Austria is following their patients up in more detail at 6, 12 and 24 weeks after discharge. So far, they have found that at 6 weeks 47% of patients are short of breath and this falls to 39% at 12 weeks. In addition, 33% have abnormal lung function suggestive of lung fibrosis, but this falls to 22% at 12 weeks. Of course, to diagnose lung fibrosis requires at CT scan of the chest and they found that CT scans suggested an interstitial lung disease (ILD) or lung fibrosis in 88% falling to 56% at 12 weeks. However, it is also important to know how much of the lung is affected, and many of the studies do not clarify this, but just comment on whether ILD is present or not. The result is that it is hard to know whether these patients had minimal or significant ILD changes on the CT scan. Clearly, Breathing Matters will be looking out for the 24 week data.

Our own experience is that of around 800 patients seen at UCLH with COVID-19, around 8% have persistent or slowly resolving CT changes at 5 months suggestive of interstitial lung involvement. Our main priority at the moment is to analyse our data from the ‘first wave’ to see how common the development of ILD/ PF is in these patients, how much of the lung is affected and what the critical contributory factors are. It may be that this virus and the enormous numbers of patients that have been infected will shed some light on the pathogenesis of other ILD/PF diseases.

We will let you know as soon as we have reviewed all these patients and their scans.

 

Clean Air Day Campaign

We are honoured to have worked with Health Awareness on the 2020 Respiratory Health Clean Air Day Campaign.

A printed publication is enclosed within every copy of the Guardian newspaper published on 8th October 2020 and the content is available online at www.healthawareness.co.uk/respiratory.

The campaign features exclusive content from key thought leaders and industry voices about respiratory conditions and external risk factors such as air pollution and COVID-19.

All You Want for Christmas is a Santa Dash

The Virtual Santa Dash is a 5K fun run to be done with friends and family/pets or competitively on your own. Take this 5K challenge anytime in November or December 2020. Do it in your running gear alone or dressed as Christmas elves with the family! Earn the offical Santa Dash Medal and goodie bag. Simply register for the event and you will be given access to the Virtual Marathon Series runners portal where you can submit your evidence before or on your run day.

The Virtual Santa Dash has a special challenge attached and requires you to dress up in Christmas fancy dress to complete it. The Virtual Marathon Series are also offering two prizes:

  1. The first one is for the fastest time in Christmas fancy dress, become the Christmas world record holder.
  2. Secondly, to the person who raises the most money for their chosen charity by Christmas Day.

They will donate £250 to the charities chosen by the 2 winners who will receive a goodies pack from their partner Run Through in the post.

All you need to do now is register – here’s how:

  1. Register here – you will receive a confirmation email to log in to the Secure Charity Portal where you can pay your registration fee [£25 covers the cost of the place and medal only and does not go to the charity].
  2. Breathing Matters will get notification that you have signed up for your challenge and will contact you – or you can contact us directly at breathingmatters@ucl.ac.uk
  3. Set up a Breathing Matters personal fundraising page.  It is up to you how much you want to raise for Breathing Matters; there is no minimum sponsorship limit.
  4. Sort out your Santa outfit and start training!!!

Run for Halloween … Virtually !!

Trick or treat for the kids this year might get the red flag, but why not do your own healthy version with a medal and goodie bag instead!  This 5K spooky run is great for everyone everywhere and is lots of fun. Take the challenge on or before Halloween – at a venue of your choice. Do it in your running gear or a spooky character from your favourite movie scene!

Simply register for the event and you will get access to the Virtual Marathon Series runners portal where you can submit your evidence before or on the big day.

The Virtual Halloween Run has a special challenge attached and asks that you dress up in fancy dress on Halloween to complete it. Quite simply, to earn the special challenge virtual medal, you will need to upload a picture of you at the end of your run in fancy dress as well as proof of your completed 5K.

The Virtual Marathon Series is offering two prizes:

  1. The first one is for the fastest time in fancy dress, become the Halloween world record holder.
  2. Secondly, to the person who raises the most money for their chosen charity by Halloween.

They will donate £250 to the 2 winners’ chosen charity who will each receive a goodies pack from their partner RunThrough in the post.

To apply for the fastest runner, you will need to enter your time through the Virtual Marathon Series portal and complete the 5K in fancy dress on Halloween.

To apply for the highest fundraiser, you will need to send an email to virtual@runforcharity.com with a link to your fundraising page no later than 1st November 2020.

All you need to do now is register – here’s how:

  1. Register here – you will receive a confirmation email to log in to the Secure Charity Portal where you can pay your registration fee [£25 covers the cost of the place and medal only and does not go to the charity].
  2. Breathing Matters will get notification that you have signed up for your challenge and will contact you – or you can contact us directly at breathingmatters@ucl.ac.uk
  3. Set up a Breathing Matters personal fundraising page.  It is up to you how much you want to raise for Breathing Matters; there is no minimum sponsorship limit.
  4. Sort out your Halloween outfit and start training!!!

September = #Breathtember

September is #Breathtember – Global Pulmonary Fibrosis Awareness Month

 Get out of Breath for #Breathtember

Tweet Tweet!

https://www.breathingmatters.co.uk/wp-content/uploads/2013/06/twitter.png

To help raise awareness, we ask that supporters tweet different challenges during September including the term ‘#Breathtember and ask their followers to retweet and share this information as widely as possible.

Think outside the box for your challenges – getting out of breath for you could mean:

  • Cycling around your local park
  • Doing a virtual 5K/10K run or walk
  • Singing until you are out of breath
  • Walking over the wondrous London bridges
  • Blowing bubbles … or windmills!
  • Or just simply walking up the stairs!

The important thing is that you tweet your challenge including the hashtag ‘#Breathtember’ to raise awareness of pulmonary fibrosis.  Add a photo if you like.  This September, we want as many people as possible to get to know what Pulmonary Fibrosis really means.

Follow us on Twitter @Breathingmatter 

Breathing Matters ILD Clinical Trials To Date

In recognition that we are now restarting all our interstitial lung disease research post-COVID-19, we thought we would re-publish our summary of research that we originally published in December 2019.

Breathing 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
  • Outcomes:
    1. Novel 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:
    2. Completed 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.

This 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 (2017)
  • Publications:
    • 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.
  • Next steps:
    1. FDG-PET 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:
    2. We and 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 reproducible.

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.

Rheumatoid 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);
  • Publications:
    • 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.

A 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.

A 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.

Understanding 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 disease.

If you are a UCLH patient and want to get involved in any of the above studies, please discuss this with your consultant.

Breathing Matters – Partner of the 2020 Respiratory Health Campaign

Breathing Matters is honoured to work with Health Awareness on the 2020 Respiratory Health campaign.

The campaign features exclusive content from key thought leaders and industry voices about respiratory conditions and external risk factors such as air pollution and COVID-19.

There are a wealth of great articles, including:

  • One person dies every hour of pulmonary fibrosis
  • Improve your quality of life with cleaner indoor air
  • Can your income make your asthma worse?
  • Breathlessness – when to seek help
  • Improving air quality around schools to protect children

A printed publication is enclosed within every copy of the Guardian newspaper and the content is available online at www.healthawareness.co.uk/respiratory.

Definitely worth a read!

 

 

 

 

Stark Facts about Pulmonary Fibrosis

  • Without treatment, 50% of Pulmonary Fibrosis [PF] patients will die within 3 years of diagnosis. Treatment extends life expectancy to 7-8 years.
  • Men are nearly twice as likely as women to suffer from PF.
  • There are 8000 new cases of PF every year in the UK.
  • 33,000 people are living with PF in the UK.
  • More than 30,000 people will be diagnosed with PF in the 27 EU countries each year.
  • PF is more common than all leukaemias combined.
  • 3-20% of people with PF have another family member with PF.
  • Most patients can be diagnosed from 1 to 12 years after their first symptoms.
  • Pulmonary fibrosis costs the NHS £88 million per year.
  • 5 million people worldwide have PF.
  • 1 in 3 PF patients are expected to die within the next 12 months.
  • There are 5,000 PF deaths per year.
  • 9,000 admissions and 86,000 hospital bed days accounted for by IPF patients per year.

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New COVID-19 Clinical Trials Funded

Professor Joanna Porter was delighted to be awarded over £2M from LifeArc to run two clinical trials in COVID-19.

The first, ATTRACT, is in collaboration with Vicore Pharma, whom we have worked with for over 10 years on developing novel approaches for pulmonary fibrosis. The drug, VP01 (Compound 21; C21) is hoped to recalibrate the renin-angiotensin- system towards repair rather than inflammation.  This should indirectly help our research into pulmonary fibrosis too.

The second study, COVASE, is a collaboration with Veni Papayannopoulos and Veronique Brilaut at The Francis Crick Institute, to investigate an approved nebulised recombinant human deoxyribonuclease I (Dornase alfa) to reduce hyperinflammation from neutrophil extracellular traps in the lungs of hospitalised participants with COVID-19.

ATTRACT is open to recruitment and COVASE will open in the next two weeks.

Here’s the LifeArc press release with more info: https://www.lifearc.org/funding/covid-19-funding/