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11th May 2023
The King’s Centre for Lung Health aims to eliminate lung disease through a better understanding of diagnostics, prevention and treatment. Here, the Centre’s director Dr Mona Bafadhel discusses these lofty ambitions and her research and practice in COPD.
Dr Mona Bafadhel is the chair of respiratory medicine at King’s College London and director of the King’s Centre for Lung Health. Launched in June 2022, the Centre’s vision is to become a hub of world-class excellence for understanding respiratory disease, focusing on innovative and inclusive research to tackle unmet global need.
This new initiative, described by Dr Bafadhel as “very exciting” and bringing with it “lots of opportunities”, is a collaboration between multiple NHS trusts in the locality, as well as its charity partner Asthma and Lung UK.
With a large population of patients and strong “cohesion and collegiality across the associated groups from the basic scientists all the way through to clinicians, nurses, pharmacists, the palliative care team”, Dr Bafadhel hopes it will lead to lots of new insights about respiratory lung disease.
We’re covering the common and the uncommon lung diseases – we have very big clinical research excellence in asthma, we’re going to set up some COPD research and we have a very big presence in physiology. There’s also work being done in sleep and ventilation, cancer, of course, and infection. Pleural-based and interstitial lung disease is also a focus area. We’re covering a lot of ground.
We’re also interested in the life course, so we’re looking to share our knowledge with colleagues from early in utero and paediatrics as well, and we will be working with our imaging colleagues too. It’s a wide breadth of different disciplines coming together for the different disease states that we’re looking at.
My main interest is in COPD, particularly COPD exacerbations. COPD probably affects one in 10 of the adult population in the UK and it’s not just a smoking disease. We’re learning a lot about these exacerbations, so these episodes or crisis moments where patients feel worse. There’s a COPD patient having one of these crisis attacks probably once every 20 seconds in this country alone, so it’s a huge health burden and a distressing time for patients. My main interest and focus for the last 15 or so years of research has been looking to try and improve how we understand these episodes and how we treat them better.
COPD is almost an umbrella term for chronic bronchitis and emphysema. The majority of COPD is caused by smoking, but we’re now recognising that the effects of air pollution – the effects of early exposure in your life – and the effects of infection may also lead to obstructive lung disease. It’s diagnosed by a classic symptom history of cough, breathlessness, sputum production and it’s confirmed by spirometry – the lung function test that we can do in community and in hospital. It’s often diagnosed later on in life, but I suspect we’re missing lots of early cases because people attribute their breathlessness to getting older or getting unfitter.
Exacerbation episodes are the greatest burden, they’re associated with worsening quality of life, worsening lung function, increased risk of needing to go to hospital and an increased risk of dying. It’s one of the greatest needs in respiratory medicine.
I could talk about COPD and eosinophils for a very long time! The eosinophil is an immune cell that everyone has, and it was largely known to be related to allergy, asthma and parasitic infections where you’d have a higher eosinophil blood count. We never really thought about the importance of eosinophil in COPD. In my research about 15 years ago, I was able to show that eosinophil in the airway correlated to eosinophil in the blood and, importantly, the eosinophil in the blood is a very good surrogate marker for telling you that you have a particular type of airway inflammation. What’s important about that? Well, we know from asthma studies that this particular airway inflammation – T2 high inflammation – indicates that someone will have the best response to inhaled corticosteroids, oral corticosteroids or monoclonal antibodies, for example.
We saw that it had exacerbations so there was a group of people who had this eosinophilic-type exacerbation and who had a better response to prednisolone. We did some proof-of-concept studies looking at that and the blood was the easiest way to test it. We’ve subsequently shown that the blood eosinophil was related to who was going to have the best response to inhaled corticosteroids in COPD and that work has been able to influence clinical guideline practice such that now, looking at the eosinophil when you’re starting to think about inhaled steroids in patients with COPD is indicated from a global point of view.
We’re not really sure yet. It’s a tough old cell, it does lots of different things and I think what we’re slowly trying to find out is how it links to what’s going on in the airway, what’s going on in the blood and how it’s affecting other organs. There are two schools of thought, one who think it actually does something and one who think it’s just a bystander. I’m in the former group, I think they do something important. We’ll try to tease it out in the next few years, I hope.
For an acute exacerbation event, I think there’s potential to look at the eosinophil count at the acute time in a point-of-care analysis. We’ve just done a study about that – it’s currently in preparation for manuscript and peer review – and really it does look like you can use a point of care analysis to tell you that someone may not need steroids. And, of course, oral steroids themselves have side effects so we’re trying to be much more personalised and precise in treatments. We’re not fully there yet, but I don’t think it’ll be too long before things change in clinical practice – the next five or 10 years, I suspect.
The studies didn’t reach their primary endpoints, so they weren’t positive in the first go for using monoclonal antibodies. The two monoclonal antibodies that have been tested with COPD so far have been mepolizumab or benralizumab and they’re not licensed yet. When people have delved down into the characteristics a bit more, there probably is a subgroup that do best, and that’ll be the group that have higher eosinophils and more exacerbations.
The trials are being redone; I know the benralizumab study is being repeated for monoclonal antibodies in COPD – that’s the RESOLUTE study. And we also have the dupilumab studies being done in COPD, so we’ve got a few more trials that will hopefully come out in the next 12-18 months that will give us more insight into whether there is a role for monoclonal antibodies in COPD. I would hope that there might be, but it’s going to be in a subgroup, it’s not going to be for everyone.
The King’s Centre for Lung Health is involved in shaping how the studies are reported and how they get started so it’s very exciting for us.
We’re currently doing an early phase study looking at the use of a monoclonal antibodies at the acute exacerbation stage. If these are positive then we’ll go on to work on the bigger trials. We’re also looking at research trying to understand the cardiovascular risk for patients with COPD, there’s work looking at readmissions in people with COPD and we’re interested in the immunology and the response people have with infections such as viruses.
We’re also interested in looking at the effect or hormones in COPD, particularly the menopause in women. There are oestrogen receptors are present in the lining of the lungs and, if there are receptors there, it must mean that oestrogen is probably playing a role and doing something. The interest has been sparked because we’ve learnt that women have a quicker loss of lung function when exposed to cigarette smoke and they’re often more severe in their disease categories when they’re diagnosed with asthma and COPD. The menopausal effect is something that we need to consider a little bit more when we’re doing our clinical trials, our basic science experiments and when we’re recruiting our patients.
I’d like us to be able to diagnose lung disease earlier. Ultimately, I’d like us to prevent it from happening. I think that requires us to understand how it happens, what the exposures are and what the interactions are at the immune level. Earlier diagnosis will be key to influence starting treatment earlier to be able to alter disease trajectory. That’s one really key aspect. Of course, what I’d really like us to do is prevent these exacerbations from happening completely, so almost have the ability for the human response to be able to manage when you have a lung disease. There are colleagues at Imperial, for example, who are looking at early COPD cohorts, so I think we’ll get lots more information on this as that data comes out.
The Covid-19 pandemic showed us that we’re now understanding how important our lungs are. We all recognise that symptoms of cough or breathlessness aren’t normal and so many of us are empowered now to go and say, ‘I’m not feeling right, we need to do some tests.’ That’s a step forward and, of course, we’re recognising the impact of viruses on lungs whether you’ve got healthy lungs or unhealthy lungs. With time, I’d like to see the next five or 10 years really transform lung health and the health of our patients.
Dr Anjali Crawshaw shares insights into her work on idiopathic pulmonary fibrosis and how AI may be able to extend the survival rates of people living with complex lung disease.
University Hospitals Birmingham NHS Foundation Trust has recently launched what it understands to be a world-first project aiming to improve the survival rates of people living with fibrotic lung disease, including idiopathic pulmonary fibrosis (IPF).
Lung disease clinicians and researchers will use sophisticated algorithms developed by the Cambridge medical data company Qureight to read patient lung scans. The goal is to help improve understanding of fibrotic lung diseases and make more accurate and earlier diagnoses, facilitating earlier treatment.
In addition, the project will analyse significant volumes of data from ethnic minority groups to address health inequalities in the system and allow for a tailored approach to treatment for these individuals.
Dr Anjali Crawshaw is consultant respiratory physician lead, Birmingham Interstitial Lung Disease Unit, University Hospitals Birmingham NHS Foundation Trust. Here, she explains why complex inflammatory and fibrotic lung diseases – her area of specialism – can be challenging to manage in clinic and how the research will help unlock valuable insights from existing patient data.
Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrotic lung disease that affects roughly 50 in every 100,000 people. It causes the lungs to become scarred, leading to cough, severe breathlessness and progressive respiratory failure. It currently has a survival time worse than most cancers.
It can be difficult to classify the disease due to the complex and varied patterns seen. In addition, deciding if this is responding to treatment, is stable or getting worse can be challenging. It is currently necessary for specialist radiology doctors to analyse CT scan images of lungs as part of the diagnosis and monitoring process, but the process can be open to interpretation bias. One of the widely accepted and published difficulties in this field, is that if you have multiple doctors looking at the same scan, you won’t always get the same answer. One of the advantages of having good quality computer standardised algorithms is that you will.
In addition to a lung doctor specialising in such lung conditions, our multidisciplinary teams involve radiologists, pathologists, specialist nurses and pharmacists who currently make a diagnosis based on the patient history, blood tests and CT imaging. In more complex cases, invasive investigations such as a telescope test into the lungs may be required, which is not without risk. This allows a biopsy to be taken, although sometimes a more invasive biopsy is still required to make a clear diagnosis. Improved imaging techniques have reduced the number of biopsies required.
There’s a shortage of specialists, which can make this process slow and difficult.
One of the problems in healthcare in general is that a lot of our data comes from white people of European descent. There’s partly an assumption that this is the data set we’ve got, and everybody’s healthcare can be extrapolated from this.
That’s not quite right, but we don’t know how that’s not quite right. For example, the lung function of a person of Indian origin born in the US may be better than a relative the same age and build born in India. We don’t really know why that is. There are lots of sociological and environmental factors that are at play here, and we don’t understand what those are.
Idiopathic pulmonary fibrosis – just one of a huge number of fibrotic lung diseases – is another example where unconscious bias may come into play. The ‘typical’ IPF patient is a 70-year-old white man, so a patient from an ethnic minority background presenting with the same symptoms may be at risk of delayed diagnosis.
I look after a lot of people with sarcoidosis who can also develop fibrotic lung disease. They are often much younger and of working age. There’s a greater prevalence in people who are black, and their disease is often more severe, but we just don’t fully understand why that is – the data is not there.
All the patients who come through our service get CT scans as part of their diagnostic process. The study algorithm will combine the data from patient scans – for example, their lung and airway volume – with lung function data from tests, blood results and demographic records.
This information will be securely and anonymously processed to deliver insights into the presentation, development and progression of IPF. We will look specifically at the similarities and differences for ethnic minority patients.
We’re a young, super-diverse city. We’re home to people from 187 different nationalities, and more than half the population is from an ethnic minority, so we are perfectly placed to be leading on this work.
Part of the reason we’re missing this data is because you need a certain amount of money and funding to conduct studies. If research is happening in rich countries that have good access to CT imaging that will, by virtue, skew the population of patients in the database as you’re using data from the patients in front of you. Places in other parts of the world have the expertise and drive to do the research, but they don’t have the funding or access to good CT imaging so it doesn’t get done.
This partnership with Qureight marks a very significant moment for our team. Patient data that truly reflects the unique diversity of Birmingham’s population will be invaluable to the planning and delivery of more equitable patient care – not just in Birmingham and the UK but internationally.
11th August 2021
Systemic sclerosis can be defined as a systemic connective tissue disease. It is characterised by small vessel vasculopathy, production of autoantibodies and dysfunctional fibroblasts, with an increased deposition of extracellular matrix. In a UK study, the prevalence of systemic sclerosis was estimated to be 19.4 per million person-years and 4.7 times more common in women. In contrast, a US study estimated prevalence of 50 – 300 cases per million. Clinically, patients present with skin thickening, Raynaud’s syndrome and polyarthralgia. Fibrosis of the lung is known to be a complication of systemic sclerosis, leading to systemic sclerosis-associated interstitial lung disease (SS-ILD) and pulmonary hypertension. The presence of system sclerosis reduces life-expectancy by 16 to 34 years and studies suggest that SS-ILD is associated with a 2.6 greater increased risk of death. However, there is a lack of data on potential biomarkers of lung function, hindering the assessment of current and future disease progression.
Some work has revealed an accumulation of myofibroblasts in fibrotic skin in patients with systemic sclerosis and a loss of intradermal adipose tissue. Furthermore, patients with systemic sclerosis have been found to have lower levels of serum adiponectin, a hormone secreted by adipose tissue. Other data has suggested that one particular adipokine, CTRP9 is elevated in patient with patients with systemic sclerosis. This led a team from the Department of Medicine, Division of Rheumatology, University of California, US, to examine whether CTRP9 could serve as a biomarker with predictive valve for pulmonary function in patients with SS-ILD. The team turned to a patient registry to retrospectively examine this relationship and included patients with documented pulmonary tests over a 48-month interval and where CTRP9 levels had been initially recorded. They split patients into a high and low group according to CTRP9 levels and set the primary outcome of interest as forced vital capacity percent predicted (FVC%), which is valid measure of disease severity in SS-ILD.
Findings
A total of 61 patients with a mean age of 53.5 years (77.3% female) were included in the analysis. Elevated circulating CTRP9 levels were associated with significantly lower FVC% levels at baseline (72% vs 80%, p = 0.02) and after 48 months (68% vs 84%, p = 0.001). In addition, the researcher sought to determine whether CTRP9 levels could predict disease stability, which they defined as less than 3% decrease in FVC% over 48 months. The analysis showed that a low baseline CTRP9 level had a sensitivity of 73% and a specificity of 45% for disease stability.
The authors discussed how their findings clearly indicated that the presence of elevated CTRP9 was associated with more severe lung disease. They concluded that CTRP9 could represent a prognostic biomarker and a possible therapeutic target for SS-ILD.
Citation
Yang MM et al. Circulating CTRP9 is associated with severity of systemic sclerosis-associated interstitial lung disease. Arthritis Care Res 2021
5th August 2021
The term interstitial lung disease (ILD) is an umbrella term to describe a group of diseases all of which are characterised by inflammation or fibrosis of the alveolar wall and impairment of gas exchange. One form of ILD is connective tissue disease-associated ILD (CTD-ILD) and which occurs in patients with a connective tissue disease such as Sjogren’s syndrome, systemic lupus erythematosus and polymyositis, with an estimated incidence of 15% of the population. Other forms of ILD include idiopathic pulmonary fibrosis (IPF) and which has an estimated worldwide prevalence of 13 to 20 cases per 100,000. The diagnosis of ILD and identification of the underlying cause can be challenging and relies upon a combination of blood, imaging and pulmonary function tests.
The precise cause of ILD is unclear although proposed aetiologies have included an imbalance between oxidant-antioxidant factors, particularly in idiopathic pulmonary fibrosis as well as an increased level of advanced glycation end-products (AGE). Furthermore, increased levels of matrix metalloproteinase-7 (MMP-7) is also involved as witnessed by elevated levels in those with IPF. Nevertheless, differentiating between CTD-ILD and other forms of ILD such as IPF is important because the treatment is different. This led a team from the Respiratory Service, University of Virgen de la Victoria Hospital, Malaga, Spain, to explore whether it was possible to use several serum molecules to differentiate between IPF and CTD-ILD. The team recruited patients with both IPF and CTD-ILD and after a single visit to the hospital, blood samples were taken together and the levels of AGE, advanced oxidation protein products (AOPP) and MMP-7 determined. The performance of each marker was assessed using the area under the receiver operating characteristic curve (AUC) and used to determine the sensitivity and specificity of each biomarker.
Findings
In total there were 73 patients, 29 with IPF and 14 CTD-ILD and 30 healthy controls. The average age of participants was not significantly different and approximately 63 years. Mean levels of AGE, AOPP and MMP-7 were all elevated in both the CTD-ILD and IPF groups compared to controls. The AUC for AGE was 0.78 (95% CI 0.60–0.97) for patients with IPF, 0.80 for AOPP and 0.96 for MMP-7. In addition, the AUC for AGE was higher for CTD-ILD than for IPF (0.95, 95% CI 0.86 – 1.0). Using MMP-7 as a biomarker, for both conditions, the sensitivity was 92.3% for IPF and 100% for CTD-ILD and the corresponding specificities were both 92.9%. However, combining the biomarkers, AGE and MMP-7, increased the sensitivity for distinguishing between IPF and CTD-ILD to 93.3% and the specificity 100%.
In their discussion, the authors noted that while all three biomarkers were elevated in patients with the different forms of ILD, the combination of two of these markers (MMP-7 and AGE) was able to differentiate between the CTD-ILD and IPF and might therefore serve as an important biomarker in clinical practice.
Citation
Cesae EC et al. Biomarkers in Differential Diagnosis of Idiopathic Pulmonary Fibrosis and Connective Tissue Disease-Associated Interstitial Lung Disease. J Clin Med 2021
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