So hello. I'm Professor Michael, a bigger I work at the world Brompton Hospital in the UK and also Imperial College delighted to be able to talk about punky exorcists. This is a slide of my disclosures, the most important one being that this program has been supported by an educational grant from since Med and I've received consultancy and lecture fees from them in addition to other companies. So what I plan to do is I plan to spend a little bit of time talking about blankets itself and the background of texas. And then I will go into more pragmatic strategies, management strategies, guidelines. And also I'll pepper the presentation with a few clinical cases as well to illustrate some of the points that I'm trying to make. And then I'll finally end with a few slides at the end just looking at the horizon and what therapies might be useful and what types of treatment may be useful in the future. So firstly what is bunky ethicists? Well, this is the irreversible damage and dilatation of the airways. And it's the end result of multiple etiologies. It used to be found with bronco grams as per this picture there. But over the last few decades it has been diagnosed with cross sectional imaging with large airways in cross section as you can see on that ct scam. Clinically it manifests itself with cough dispute and production more current chest infections. So how common is it? Well, this has changed over the last decade or so. In 2005. A study from the us. Looking at insurance returns suggested that the prevalence was about 52 per 100,000 adults in the US. But more recent studies have suggested that it's actually a lot more prevalent than that 10 times as much. And this study illustrated here from jenny Quint, published in the E R. J, shows that actually it's about 500 per 100,000. Looking at primary care databases and those values get much higher the older the patient gas as per the graph. In addition to being more prevalent and more common than previously thought, we also know that blanket cyst has a significant disease burden both to the individual but also to healthcare as a whole. I quite like to talk about this study which was really an audit here at the top. We have 100 patients followed over six months And that produced 321 clinic visits really again, just illustrating how much healthcare burden is affected by bronchi etc. In the study I mentioned previously with US insurance returns, blankets, sis lead to a greater greater inpatient stay and a greater cost per patient than other common chronic diseases such as cardiac failure and diabetes. And this is more recent data from the embark european bronchitis registry. This is a very successful blankets. This registry of over 12,000 patients now in over 40 countries as shown on the map and there the majority of patients are having multiple exacerbations. Pierre as can be seen on the pie chart. And finally, in addition to morbidity, Patients have an increased mortality. And in 2010, a study suggested that this mortality was in fact increasing. So hopefully I've illustrated that blankets is is actually important. It's more common than we think. And it has significant effects both on the individual, but also on the health care. So looking at it in a little bit more detail, what is the pathogenesis now, this is a vicious cycle hypothesis that was put forward by one of my predecessors at the Brompton peter cole and has really stood the test of time. And the supposition is that you can enter the cycle at any point through various causes of bronchi, etc. But then for example, you get microbial infection which causes inflammation. The inflammation then leads to more damage, which further impairs lung defenses and so on and so forth. As you go around as you go around starting at any of these points, this is a good way to think about bank yet, sis And it has been looked at in more detail and further authors have suggested it's even more complex than that with the same groups of of disease mechanism causing multiple effects at multiple different sites and the vicious circle becoming in fact a vicious vortex. And it's quite useful to use this as a model for individual causes. And I mentioned that right at the beginning that it's the end result of lots of heterogeneous conditions. And this was a study in our center in 2007 showing different causes of bronchitis. And you can see that you may enter it with microbial infections such as with micro bacterial infection. You may enter it with inflammation such as with ABP, a allergic broncho, pulmonary tuberculosis or ulcerative colitis. You may enter it with impaired lung defenses. So that may be secondary to problems with mucus clearance, such as primary biliary dyskinesia or cystic fibrosis. Or it may be due to tissue damage such as radiotherapy or having some physical blockage of your tubes, such as an aspirated bead. The other thing just to mention within the background of Bankia texas is that over the last few years has been the development of severity scores and these are various variables which put together either the facets score or the blanket's severity index score, which put together enable physician to determine how severe the blankets this is and the more of these negative prognostic factors the patient has, the higher the score is and this for the BSI has been shown to be related to increased mortality with higher scores, increased hospital admissions, increased exacerbations per year and increased symptoms on the ST George's respiratory questionnaire. And just to give you an idea of how the patient's split between the various categories of mild moderate and severe blankets. The severity index. It's about a third in each group using that embark registry data that I mentioned before. So that leads on from the background of Bankia texas. How about the management? Well, the management really follows the two main guidelines. The first one being the British Thoracic Society guidelines published in 2019 and the initial won the european respiratory society guidelines published a couple of years before that the management really follows the idea of this vicious cycle and the idea is that you try and break the cycle at various points. So the first important thing is to treat the underlying cause. Going back to the various courses that I showed before, different etiologies may need different treatments and we'll talk about that a little bit later with some of our cases. But as an example if somebody has immunoglobulin deficiency or common variable immune deficiency, then they need treatment with immunoglobulin replacement. If somebody has bronchitis is secondary to micro bacterial infection, then they may need specific micro bacterial infection and so forth. So treating the underlying cause is extremely important. After that. We would look at airway clearance to try and break the cycle between the impaired lung defense and getting infected. You would have antibiotics to break this cycle here and I'll also talk a little bit when we talk about future management about anti inflammatory agents trying to break the cycle there. So what evidence is there for all of these? Well, the evidence based surprisingly is not that strong for airway clearance. There has been one relatively recent study a few years ago now looking at the improvement of patients with physiotherapy compared to no physiotherapy. But the numbers were very small. I think there were only about 40 patients in this study. Other adjuncts to physiotherapy to help our clearance has been looked at. Mannitol has been looked at in a phase three and phase two study and hypersonic saline has been looked at in various small studies but both of these have had quite varied results with the mannitol study failing in its primary endpoints. There are continuing ongoing studies. One NIH our National Institute of Health Research in the UK study looking at hypersonic Saillant of carbon Sistine. And there are other studies including Phase Two study looking at CFTR channels to try and improve mucus clearance even in those without cystic fibrosis. How about the second group antibiotics? Well this has been where the most studies have been. There were three positive mackerel I'd studies that were published closely together looking at azithromycin and erythromycin, all of which had a positive effect in reduction of exacerbation number. Um and hence mackerel. IEDs have been used within guidelines and within practice, which I'll talk about later in held antibiotics are also used. But actually there isn't a good deal of good quality evidence in Phase three studies for inhaled antibiotics, there's been lots of positive Phase Two data showing bacterial load reduction But Phase three studies looking at exacerbation reduction or other endpoints such as quality of life have failed presently to meet their primary endpoints. And that's Austrian am and ciprofloxacin, both dry powder and like so more And there's an ongoing Phase three permits and study and finally anti inflammatories. The evidence for um inhaled steroids is again not particularly high. Who was one Phase 2 study, which I'll talk about later looking at spencer khatib to reduce proteus is in bronchi ethicists and the several ongoing studies again that will come to talk about a bit later with future management. But the bottom line is despite all these studies at present, there are no licensed treatments for bronchi etc. Excluding cystic fibrosis and multiple failed clinical trials to reach their primary endpoints. So why is this? So one reason may be the wrong type of patient. The chart at the bottom right of this graph Is interesting and it shows along the X-axis all the different clinical studies that have been done Phase three clinical studies and looking at different clinical cohorts in real life in various centers. And you can see that the inclusion and exclusion criteria for the clinical studies. I mean that actually the only 20% or in fact less than 20% in many studies of patients in the real cohorts are eligible. So are we choosing the right patients and together with that the heterogeneity of the condition is important. As I mentioned, both the beginning and later on bronchitis is the end result of multiple different etiologies and hence the underlying pathology Andy geology may be different. And so treatments may not work in all of these groups of patients. And finally are we looking for the wrong end points? So we're often using endpoints such as exacerbation mates quality of life even perhaps the v. one. But studies have shown that actually looking at some of these studies that have been, there can be discordant of these endpoints and hence choosing the right endpoint is really important. So where does that leave us? So despite the lack of good quality? Phase three um evidence the guidelines. This is from the british thoracic society guidance suggests that for bunkie artists we need to treat the underlying cause and then ensure that the patient is optimized. So are they having good airway clearance and physiotherapy? Are they getting problems? Antibiotics for exacerbations. Do they have self management plans? Are they getting vaccinations? If despite this they're still having recurrent infections and despite optimization of their physiotherapy then long term antibiotics should be locked up with pseudomonas. Either long term anti pseudomonas inhaled antibiotic or long term mac relied and if other antibiotic if other pathogens rather than pseudomonas then mackerel I'd maybe useful or targeted antibiotics If despite that patients are still struggling then perhaps the combination of both inhaled and long term mackerel IEDs and if they're still struggling with recurrent exacerbations after that. Then the consideration of recurrent regular intravenous antibiotics. So now I'd like to take a bit of time to really illustrate some of the points that I've made with regards to both the management, the underlying diagnosis, the etiology and what to do with some of these patients that are perhaps struggling With four cases that really highlight slightly different things. The first case is a 20 year old female who as well as a child and started to develop a cough with sputum production. At the age of 14, She was referred to a local hospital at 17 and had a CT Scan. The cT scan showed significant banki axis and bunker vascular consolidation of mucus plugging in the lingual er and left lower lobe. And she was actually at that stage referred to a surgeon who removed these two lobes, noticing that the rest of the lungs were clear, the patient was well but relapsed a few months later developing too, 3rd of a pot of green sputum, 4- five infections per year. And she ended up having a repeat ct scan. This unfortunately showed the development of new bronchi actresses in the right middle lobe. She was then referred to my center and we did the ideological investigations and found that she had very low and um and she was diagnosed with common variable immune deficiency. She was originally started on azithromycin and then she was started on intravenous immunoglobulin therapy which has been shifted to subcutaneous immunoglobulin therapy and when her trough eeg was sufficient, who is it promising was discontinued. And she's been really well since then. This case really highlights the importance of finding an underlying diagnosis for bronchitis if that is possible because the management is very different. And certainly surgery probably wouldn't be the first line of treatment without replacing the immunoglobulin. Moving on now to case two This is a 63 year old female who had asthma as a child, developed cough and sputum In her late 40s And then had bronchitis is diagnosed in 2009 and you can see that we've dilated airways here in both lower lobes quite mild. She had the various ideological investigations that I mentioned and she was deemed idiopathic bronchi etc. She grew pseudomonas but was relatively stable with wanted to infections Pierre. However, over the last couple of years she started to deteriorate more sputum, more shortness of breath, more infections and less effective. Each antibiotic course on her on her exacerbation. So we again looked at some other factors and we looked at her I. G. E. Value and as you can see where this had been negative and normal throughout her life this would suddenly increased significantly To over 7000. So she actually had a BPA allergic bunker pulmonary tuberculosis which wasn't the cause of her original bronchi texas but had come on as an added complication of bronchitis which often happens. And the treatment in this case was with steroids and she had a significant I. G. G. G. Response and then her clinical response followed. This is case to an illustration of an additional diagnosis linked to bronchi exorcist but separate from the original etiology. Again leading to different trees. This moves me on to case three. This is a 78 year old female E. M. This patient as well as a child and a young adult But it had an eight year history of a productive cough. Lots of infections per year. Widespread Bankia assists with again a lot of bunker vascular consolidation and modular change. As shown on the CT scan. Her host defense screen like the previous patient was unremarkable although she did have some reflux symptoms in this case we put her on a proton pump inhibitor, gave physiotherapy review and had significant increase in physiotherapy with adjuncts including an acapella hypersonic saline and the introduction of some positive pressure physiotherapy And this patient had a significant improvement and the reduction in her exacerbation, mate 2 2 infections per year. So this highlights some of the management steps that I mentioned before after the underlying diagnosis or perhaps the additional diagnosis. You then want to ensure that there's optimization the first thing to optimize his physiotherapy. Another external things such as reflux. And we did that here and share the clinical and radiological improvement. The final cases case four. This is a 53 year old female JW. Her underlying etiology was primary salary dyskinesia which is a condition a genetic condition, autism or recessive normally where the sillier which line there are spiritual tracks, don't beat properly and hence mucus clearance is not adequate and then that leads to a lack of clearance and round the vicious cycle. As I mentioned before, This patient had a deterioration at about the age of 40 and develop multiple infections with pseudomonas. We tried to eradicate the pseudomonas but that was unsuccessful and we put him on long term antibiotics. Originally column mission and although there was some stabilization was still increased infections and in addition to increasing a physiotherapy, we added as if we're missing. So this patient now had both column is inhaled and as if her mission and despite that she had repeated need for antibiotics. And we started needing several admissions for intravenous therapy per year. She had anxiety and depression. Her management was optimist as much as we could see. Very bad disease as you can see on the cT scan when we started introducing cyclical intravenous antibiotics. So that would mean a patient would come in every 2-3 months, have 10 days to weeks of intravenous antibiotics and then had a period of reasonably good health before she would start to deteriorate a little bit before her next course was due and this would give her a little bit of structure to her life. She was able to live her life without fear of when the next exacerbation would come because she had relatively good health in between exacerbations. This is case four really an example, again, with the guidelines that I've mentioned of how to start adding on therapies for patients with significant disease. That's where we are at the moment. And I've mentioned already the problem with some of the evidence and the lack of positive primary endpoints with a lot of the clinical studies and this kind of brings us on to what may change or how may future management differ. Going forward. And the first idea is again, trying to get away from the heterogeneity of bronchitis and lumping everybody together and looking a bit more into into treatable traits. And there's some evidence that treatable traits may be useful within bronchi exist. And there has been studies which have post hoc looked at perhaps why some of these studies have failed. So the mannitol study failed in the primary endpoint, but actually on a post hoc analysis of looking at patients with high baseline symptoms, they had a positive outcome in the Austrian am inhaled study which used um a quality of life endpoint when patients were locked up with high bacterial loads. Um Then again, those patients had positive endpoints and then inhaled steroids, patients with high bloodier sinful counts seem to do better. So this seems to suggest that actually, if you cut through the heterogeneity of blanket's patients, there will be groups of patients within that, that will benefit from some of these different managements and actually finding the right patient for the right treatment or rather the right treatment for the right patient. Maybe the way that management goes in the future to investigating treatable traits. Looking for those with frequent exacerbations and then perhaps with those were very infection acting, inhaled antibiotic. Those would be a sin ophelia corticosteroids, inhaled mucus plugging mucus active drugs etcetera etcetera. And that was highlighted nicely in this review article mentioned below. So just the last bit of the talk now what kind of future management's might we target? I've mentioned a few times in the talk about reduction of inflammation or anti inflammatory agents and blankets is typically the pathogenesis is thought to be due to neutrophils damage and high levels of neutrophils within the airways. And you'd feel certainly are central to Banki axis and they can cause damage by various different mechanisms, acidosis, degranulation, reactive oxygen species, cytokines, neutral nets. Um And Syrian protease is such as neutral or last days. Pr three and cafes G. And we know that looking at the protease is that the amount of neutral last days which is the most common protein is associated with the extent the exacerbation mate lung function decline and bacterial load in Banki axis. Various studies by James charm is showing that and you can see here higher levels of neutrophils last days relate to higher levels of blankets a severity Using the bunker, its severity index higher levels of neutral a last days leading to increased um exacerbation rates again on on the bottom right panel and higher levels of neutral or last days related to higher levels of bacterial loads. So targeting inflammation or targeting protein raises or neutral last days may seem a sensible thing to do. So what have studies shown? So a lot of studies have been small, one has looked at blocking neutrophils recruitment, but there was some concern with increasing infections exacerbations in that study neutral. The last days inhibition directly has been tested in a couple of small studies in bronchitis with variable effects. But there has been one study which has looked at DPP one inhibition and Brent's talkative is an oval selective and competitive inhibitor of that. And what that does is it stops the neutral maturation within the bone marrow to stop some of the development of some of these protease is for release later on. And that was the basis of this space to trial that was published in the new England Journal. And here you can surely see that doses of Brenton khatib reduced the neutral elastics in the sputum, but also from an end point of view, they reduce the proportion of patients with exacerbations and time to the next exacerbation in particular. And so this is a study which is now in phase three. Um, and so hopefully we'll get the results lead to them. So finally the other aspect, in addition to targeting information with the neutral film. there has been some evidence that perhaps in some patients again, looking at treatable trades, dear santa fill may be important. And there has been a recent study out in the Blue journal showing that actually if patient cohorts were looked at, Then there's about 20% of patients that have high ear cinephile counts in the blood Of greater than 300 CPU l. And there seems to be potentially some impact of highest interval counts on clinical outcome. And this is again a panel from the same paper suggesting that in patients who did the original promise study of inhale column is in those with higher ears. NFL County did worse. And there was as I mentioned before, some evidence between inhaled steroids and patients with high blood either sinful counts. There has also been some pilot data looking at the use of anti I. L. Five or L. Five receptor antagonists in some patients. And there is also a phase three study undergoing at the moment um looking at Ben melissa mob. So that brings me to the end of my talk. I hope that's I've managed to persuade you that blankets this is important. There's a significant number of patients with bronchial and there's a significant burden both to the individual but also to healthcare systems, there's definitely a significant unmet need, although there are guidelines, there are no licensed products bronchi artists at the moment. And so there really is a need for for products in this space. And it may be that actually future treatment starts looking at the idea of treatable traits and and treating particular groups of patients going forward. So the hope is that there's more successful clinical trials and licensed therapy is going forward and the space has moved on significantly over the last decade. There's a significant increase, both from industry and from research groups, but also from clinicians as well. And so things have moved forward a lot to to develop the ideas and clinical trials to this point. But there is still an unmet need that needs to be filled. Thank you very much. I hope you found that useful.
