Video NCFBE: Clinical Evaluation and Diagnosis, Disease Management Overview, Risk Stratification, and the Role of DPP-1 Inhibition in Managing Exacerbations Play Pause Volume Quality 720P 720P 576P Fullscreen Captions Transcript Chapters Slides NCFBE: Clinical Evaluation and Diagnosis, Disease Management Overview, Risk Stratification, and the Role of DPP-1 Inhibition in Managing Exacerbations Overview Hello everyone. My name is Dave Griffith, I'm professor of medicine at national jewish health in Denver colorado And I'm gonna talk to you today a little bit about thesis. So this presentation is entitled non cystic fibrosis, bronchial texas, clinical evaluation and diagnosis. Disease management, overview, risk stratification and the role of DPP one inhibition and managing exacerbations. This is a C. M. E. Activity jointly provided by the University of Massachusetts Medical School and cm Education resources. It is supported by an educational grant from in smith. So bronchitis is, the word itself is derived from the greek words broncos meaning airway and ect Asus meaning widening. So the word defines it, the syndrome itself dilated or widen bronchial tubes. It is a chronic lung condition defined as the abnormal irreversible dilatation of the bronchi where the elastic and muscular tissue is destroyed by acute or chronic inflammation and infection. Airways of the lungs become dilated or widened, leading to a build up of excess mucus that can make the lungs more vulnerable to infection and in fact they do make the lung more vulnerable to infection, bronchitis is is not well understood. I think in the medical community at large. And one thing I'd like to point out is that um it is almost a non specific response to chronic severe or recurrent inflammation. That is bronchitis is per se is more a description than a diagnosis because it doesn't tell you how you got to the point where you have bronchitis and we will discuss that uh some as we go along. Um When do suspect bronchial emphasis. Uh It's usually associated with productive cough. Him, a texas is very common. It occurs to some degree in almost every patient with bronchitis is, but I think the real indicator is recurrent infectious exacerbations and the frequent use of antibiotics for respiratory infections. There is some overlap with other pulmonary diseases, particularly COPD and to some degree asthma. It can be a little tricky because bronco spasm can be part of rocky ethicist. And of course, as I mentioned, it is usually associated with some other process. It is a manifestation of the lung inflammation from other diseases. So it can be congenital or hereditary associated with autoimmune diseases, uh immune deficiency syndromes and gastrointestinal problems such as esophageal reflux, I would add here that I think it should be part of the chronic cough. Evaluation, chronic cough is defined as cough for more than eight weeks, which doesn't sound like very long. But I think a lot of people with bronchial ethicist get overlooked because they're treated for things like asthma, sinusitis and esophageal reflux. The real key in in my mind is the recurrent infectious exacerbations, the frequent use of antibiotics. If you have a patient who has the need for antibiotics for respiratory infections for more than one episode per year, then that would be uh an indicator and of course there there is a unique uh excuse me, there is an almost unique appearance to a lot of the patients who have bronchitis and those are women usually postmenopausal who are relatively tall and thin and someone with that morpho type and a chronic cough. I would strongly suspect bronchitis epidemiologically, it's not a reportable disease of course. So the numbers are only estimates. There probably north of half a million people in the United States with cactuses, two thirds that are women. And as I mentioned, most of these women are postmenopausal. The incidents does appear to be increasing as is the prevalence because there is no way to eliminate the process once it's diagnosed. So the incidents just sort of continues to add to the, to the prevalence. And we're seeing similar increases across the globe frankly, in terms of the diagnosis, this is in this cartoon on on the left you see a normal bronchus, but then on the right you see bronchus that's dilated and there is mucus in the airway. So several things happen when bronchitis occurs. One is there a serial dysfunction which is the the sillier, the mucus earlier is the mucus Salieri elevator for mucus, secondly the mucus glands proliferate and then third, the bronchus dilates and the end result is that you you cannot clear the mucus from the lungs and that unfortunately is the critical element in setting the chain of events that produces more so bronchitis is on the right radiographic lee, there are some clues to ideology based on where the emphasis is most evident. So in the upper lobe you think of cystic fibrosis or prior tuberculosis In the mid long. Again it could be cf allergic broncho, pulmonary aspergillus. Isse trachea, bronchial medley and in the lower lobes you think about prior childhood infections, aspirations, immunodeficiency and alpha one. Any trips in deficiency. None of those is completely specific. It's just particularly the upper lobe involvement with CF I think is very useful in terms of pathogenesis. There is uh the prevailing hypothesis is the vicious cycle hypothesis. So you have an initial infection or uh some type of inflammatory stimulus which causes neutrophils, inflammation and release of neutrophils proteus is there is airway destruction and distortion which is this loss of integrity of the bronchial wall with bronchial widening and bronchial assist, as I mentioned, abnormal mucus clearance due to the Salieri dysfunction and the excess mucus production. And then you get the invasion of the microorganisms with bacterial colonization particularly and that feeds back into the neutrophils inflammation. The pathogenic microorganisms are very strong stimulus to the recruitment of neutrophils into the airways. So as you see it is in fact a vicious cycle, the role of neutrophils is increasingly seen as important in the pathogenesis of bronchitis, particularly the release of Neutra filic Syrian proteus is that includes neutrophils, lasts milo peroxide says Matrix metallic protean Asus stepson's antimicrobial peptides and Neutra filic derived D. N. A. I won't go through the schematic on the right but it shows the interaction of all of these components in the neutrophils mediated inflammation interestingly, a third of patients may have eosinophilic inflammation which may be associated with bronco spasm. In addition to the other manifestations of bronchial basis. So the reason I wanted to show this slide is that on the left, you see the vicious cycle that we talked about, it's broken down a little bit more in this uh schematic on the right. And the point of this is that you have four aspects of the path of physiology. There's epithelial dysfunction, mucus hyper secretion and Salieri dysfunction, which we talked about neutral filic inflammation, t cell inflammation and local or systemic immunodeficiency chronic infection, bacterial virulence factors and bronchi ethicists and lung dysfunction. But the point being is that any one of these feeds back into the other three. So it is quite a potent if you will vicious cycle once, once it's started all of the manifestations. All of these path of physiologic events exacerbate every other path of physiologic event. As I say, quite a potent vicious cycle phenomenon. So as I mentioned, there are a number of ideologies of bronchitis ist I think historically post infectious has been the most common and tuberculosis specifically has been a common cause of brock texas, I would say in the United States at the turn of the 20th century. Probably 90 plus percent of the bronchi emphasis was post infectious. Now we also see it with hereditary or genetic abnormalities like cystic fibrosis alpha one. Any trips and efficiency and primary Salieri dyskinesia immunologically primary immune deficiency, common variable immunodeficiency and some bone marrow deficiencies. Autoimmune processes are relatively common, including shogren syndrome and rheumatoid arthritis. And interesting even inflammatory bowel disease can be associated with bronchitis, uh esophageal reflux or dysplasia with aspiration. Um, it's unclear how much of the bronchial basis that we see is related to aspiration. It's certainly easy to identify in these patients. My view of it is that whether or not it's the primary ideological factor. I think it is certainly an exacerbating factor. So identifying it can still be helpful even if it's not the initiating factor for the bronchi ect assist. And lastly, we have the idiopathic category which I think about half of our patients, we don't come up with a specific diagnosis. I would only point out that this idiopathic category is I think going to evolve into a genetic category. So, for instance, the women that we talked about the relatively tall, thin postmenopausal female may not have a single, if you will smoking gun mutation, like a cystic fibrosis gene mutation to account for the Bronx texas, but they may have multiple, relatively innocuous mutations all having to do with mucus Salieri clearance, some of which probably results in brock texas. So I think as we get better at doing our analysis of genetic abnormalities. More of these so called idiopathic patients will will turn out to have genetic problems. So usually a high resolution cT is necessary to confirm the diagnosis. Chest radiographs often are not sensitive enough, especially for early broadcasts. This is, it progresses. There are certainly chest radiographic abnormalities that are uh diagnostic. But essentially all of these patients require chest cT scheme sputum cultures for bacteria, micro bacteria and fungi, pulmonary function, testing a cbc immunoglobulin levels and where appropriate, allergic broncho pulmonary aspergillus is evaluation. I put this slide back up because patient education is just absolutely essential project. IsIS is not part of the average patients vocabulary. Most of them can't pronounce it. They don't know what it is, they're afraid of it. It's interesting to me that many patients feel like the diagnosis is a life threatening diagnosis which in the vast majority of cases it is not. But I will say that at least half of any interaction I have with a new patient who has brought texas has to do with explaining the process. And I think allaying some of their fears about what will happen because they have brock texas. It is generally extremely slowly progressive process now with the caveat that certainly there are rapidly progressive forms of broadcasts such as with cystic fibrosis. But nevertheless, I think the perhaps the most important thing a physician can do with the newly diagnosed projects this patient just explain the process which takes away a lot of anxiety from the patients. So for possible genetic ideologies, you would think about cystic fibrosis and someone who has concomitant sinus disease of course that can occur also with BCD pancreatitis, gI dysfunction in male infertility. Also finding staff in the sputum or Burkholder area would be more common in cF than non cf bronchial emphasis, primary biliary dyskinesia is still a difficult diagnosis. There's not one diagnostic test except perhaps an abnormal nasal scraping alpha one. Any trips and deficiency can be associated with emphysema or hepatic disease. It's relatively easy to diagnose actually obtaining an alpha one. Any trips and level and phenotype can be done at no charge to the patient. Um And then in terms of altered immune response response is A B P A C B I. D and C. L. L. Um Against the pattern of bronchitis is the onset of bronchi texas, particularly at a young age, might steer you toward one of these genetic ideologies we discussed, some of the autoimmune diseases, rheumatoid arthritis. Sjogren's syndrome and inflammatory bowel disease. Um focal bronchitis is can occur as a result of airway obstruction from a tumor or foreign body. Post infectious is also relatively should be relatively focal, lower, low predominant. Think about dysplasia, reflux and aspiration and then there are structural abnormalities such as Mounier Kuhn syndrome sarcoidosis and occasionally with asthma and COPD actually some level of bronchial cactuses can be found in up to 40% of patients with COPD, presumably related to the chronic airways. I'm sorry, presumably related to the chronic airway inflammation. If you think about some of these specific causes of bronchitis. Further testing particularly may be important in identifying those causes. So as I mentioned, a younger patient, someone who has a family history of similar respiratory symptoms or bronchial basis multi organ disease, as with Alpha one and hepatic disease, or cF and pancreatic disease. And as mentioned, the presence of specific pathogens, particularly for CF. If someone has other sites of infection that might suggest a systemic immunodeficiency focal disease, bronchoscopy might be helpful for excluding airway obstruction and then in lower low predominant disease. Uh and Asafa graham or barium swallow or even swallow analysis with a speech pathologist may be helpful. So um in terms of the basic evaluation, we've talked about that. The extended evaluation, as I mentioned, the alpha one. Any trips and level and phenotype can be obtained at no charge to the patient cystic fibrosis testing, usually screening with a sweat, chloride and then CFTR mutation analysis, um autoimmune disease testing and the G. I work up that we've talked about this is uh this constellation of test is pretty much how we approach most of our patients here at national jewish health looking for uh an identifiable cause of of the bronchi axis, but also a treatable cause. So for instance, Alpha one anti trips and augmentation is available. It's not clear how much it benefits patients with bronchial exorcist as opposed to emphysema. However, it may also be helpful for patients who have other infections like non tuberculosis, michael bacterial disease. And of course there are all of the new CFTR modulators for patients with cystic fibrosis. In some of those patients, the modulators can actually be transformative. Now, I think it's important to remember that most of our patients with non cystic fibrosis projects is don't have cf or have our hetero zygote for a CFTR mutation. My opinion is that more of those patients in the future will be considered for the modulators as the use of those modulators expands. But that's that's fairly far off I would I would say. But I would still consider it a treatable process now because of modulator therapy, A number of bacterial pathogens are common in bronchitis is patients. I think it's worth pointing out that most of our patients have polly microbial colonization of their trachea bronchial tree with bacteria so that it's not one as opposed to another. There just seems to be one predominant one. When we do our cultures, pseudomonas is generally the most common commonly isolated bacteria in texas but you can see Demopoulos staff more rocks ella are also found. And this list is certainly incomplete because we see other gram negative rods like Klebsiella and proteus and then we see more troublesome organisms like Stennett, Ramona's and chroma factor. Those are sometimes extraordinarily difficult to treat. I know it's hard to imagine that pseudomonas might be the easiest of these bacterial pathogens to manage once it's recovered, but it is certainly important to know what bacterial pathogens grow from a patient's sputum. So I cannot emphasize enough how important patient education is your patient is going to come into you knowing essentially nothing about bronchi texas and they are just extraordinarily grateful to be in contact with someone who can explain to them what's going on. Um And it's important to understand from the patient what kind of impact the disease has in terms of their symptoms in assessing the frequency of their exacerbations. Certainly the cT will help define the extent of disease. Pulmonary function. Testing also is helpful for evaluating the impact of the disease on the patient's quality of life. So the goals are reduced exacerbations of bronchitis ist try to control symptoms and improve the quality of life. And I think those two are easily the most important for a lot of these patients. The cough is just absolutely debilitating. So controlling symptoms and improving quality of life I think is number one, you've got to make the patient feel better if if possible and then there's preserving lung function and reducing mortality. Now, fortunately for most patients with bronchial exorcist, lung function stays relatively good um and does not fall rapidly and also mortality from brock texas per se is relatively low. It's more related to complications such as pneumonia, but again, I cannot emphasize enough what the patient wants is to cough less and to be more active to have less fatigue and in some cases to be able to gain weight. That's also important. So milo, sorry, my phone is ringing. Let me let me grab it second. Go ahead. Thanks a lot. Okay bye bye. Sorry milo, that that's it. Okay, go ahead. With regard to exacerbations, we'd like to decrease the number of exacerbations these patients have and reduce their risk for hospitalization. So in managing bronchi exorcists again we want to target the vicious cycle or I think as it's better described this vicious vortex that we're all of the factors exacerbating Brockie actresses feed into one another. So obviously if there's an underlying disease we can treat, we want to do that. We want to try to improve airway clearance and we'll talk about modalities for that. There are anti inflammatory therapies. Antibiotics are important. It's important to treat exacerbations uh and all of these things are necessary in order to help patients manage their practices. So as we said, the step one is to treat the underlying disease. Um and if you can for the genetic disorders there are for cystic fibrosis, the CFTR modulators, ralph want any trips and efficiency, there's alpha one any trips of augmentation for primary Salieri dyskinesia. There's still not a therapy for the underlying process. Unfortunately for immunoglobulin deficiency. Of course there is immunoglobulin replacement therapy and then there are a number of modalities for treating autoimmune diseases. Now of course many of those modalities involved immune suppression which affects other aspects of bronchi excesses such as michael bacterial disease, but we won't get into that for now. But the other some benefits of those therapies can accrue for the bronchitis ist per se. So in terms of airway clearance, we hope to reduce cough overall and hopefully reduce the work of breathing and and reduce dysosmia. I think the benefit of airway clearance is more in the longer term strategies to reduce airway damage. We want to interrupt that vicious cycle that we've seen several times and and break the link between infection and inflammation. And so the key element in breaking that link is minimizing or reducing the amount of secretions or mucus that's retained in the airway because that's square one, that's where the organisms are attracted. So, as I say, I do think that interrupting a vicious cycle and breaking the link between infection and inflammation is absolutely critical. We also hope to reduce exacerbations. And of course, as I mentioned, improve the quality of life. We want to decrease the amount of coughing that these patients do when they're not using their airway clearance measures. So this is a list of airway clearance techniques. Now, these are the physical techniques and I would point out that uh there is a bronchi excesses toolbox website and under optimal modality, you see, you see whatever the patient will do uh and that's that's obviously number one, you know, it won't help if you teach the patient how to huff cough if they're not going to do it now. This is just sort of the shallow into the pool. There are of course airway clearance devices including the positive airway pressure, positive expository pressure devices like the Arabic A device and then the and then the vibrate. Torrey external devices such as the vest. And I think, you know, particularly the p P devices are useful vest can sometimes be helpful, but they're not for everyone. And particularly some of our more frail female patients. Um in terms of pharmacologic agents for airway clearance, I don't think venison or do very much. I don't think they're harmful, but there's really no data to support their use. Similarly, bronchodilators I think are helpful, particularly in those patients who have the eosinophilic inflammation associated with their brand ketosis. In this little system, I have never seen any data that suggests it is particularly helpful. So, of those two bronchodilators and n acetyl system, I think brock a dilator are demonstrably helpful in patients who have bronco spasm or reversible airflow obstruction, but otherwise I'm not sure they add much. The DNA's was tested in non cf bronchitis in the past and it was not found to be helpful. As a matter of fact it was assessed that it was harmful in these patients. I don't think that that that that has stood the test of time. But the point being is that even though it's definitely helpful in cf patients, it is not indicated for non cf geneticists, hyper tonic saline I think is the backbone of our pharmacologic intervention for Bronx texas, an airway clearance. There's at least one small positive study in this population. I will say that my general approach to these patients is uh the use of a device like the P. E. P. Uh my general approach to these patients is usually a pEP device in addition to the hyper tonic saline, that's generally where I like to start. If that is ineffective then I would go to a vest and then there are even newer strategies and newer devices which can be helpful but only if patients fail the P. E. P. Device to saline and the best and then mannitol, which is another hyper as Mueller product has not been shown to be effective. Something I think that gets lost sometimes is pulmonary rehab and exercise. And as you can see from the slide, these programs are quite helpful. They improve the six minute walk, they improve the six minute walk distance, the distance score and the quality of life index. I think we sometimes forget about the pulmonary rehab for this group of people. We think about it often in the COPD group, but I think it's underutilized and in terms of data that support it's used. There's more data for this than almost anything else that we do and then um anti inflammatory therapies. I think most folks are familiar with the use of macro leads in this setting. Studies have shown that long term use of mackerel eyes, decreases bronchitis exacerbations. Um I think it's well known that the macro lives in addition to their antibacterial properties also have immune modulating properties. And those are helpful not just in texas but also in processes such as COPD for preventing exacerbations and they seem to be safe for long term use. Now inhale cortical steroids I think are a different story. There's really not. There's not the wealth of data about the benefit of inhaled corticosteroids that there is with the macro lives. And also I think there's good data that the inhaled cortical steroids promote micro bacterial infections. I avoid inhaled cortical steroids and brock texas patients unless there is a specific indication such as asthma or perhaps even eosinophilic brock texas with bronco spasm but in general if I'm going to use bronchodilators, I just use bronchodilators and not inhaled cortical steroid. Um and we talked about the uh the bacterial flora in these patients and antibiotics of course are chosen to target the predominant pathogen in a patient's sputum, both acutely orally and intravenously for exacerbations and chronically with inhaled antibiotics to suppress a particular organism and reduce the number of exacerbations, pseudomonas being the most common which is the target of the inhaled antibiotic. So when you think about inhaled antibiotic. Well it's a little controversial. I think most experts would agree that at least two and maybe three exacerbations per year would be an indication. The evidence for the efficacy is almost exclusively in pseudomonas. I think also I would consider that patients who are using airway clearance and still remain symptomatic day to day, not necessarily frequent exacerbations, but just refractory cough. And I have tried that in a number of patients with some success. So it doesn't mean you have to have multiple exacerbations if your quality of life is just extremely poor based on persistent cough and you have pseudomonas say then I think a trial of an inhaled antibiotic is good. What about infections with other organisms? Well, I have I try that too. Again, variable success. Part of the problem is there are not good inhaled antibiotics for him, Oculus influenza and staph aureus or even Stennett Ramona's. If you look at the available antibiotics, their spectrum doesn't necessarily include these organisms. Now, the one that I think has value for Senator Ramona's potentially is coolest stint and we'll talk a little bit more about that. But this is still an area that's where patient management is difficult. And then of course there are infections with other organisms like michael bacteria and no cardia and fungi which require other specific antimicrobial approaches other than the antibacterial antibiotics for pseudomonas and of course costs and insurance coverage are a major problem for the inhaled antibiotics. So this is one approach. The first approach might be use of macro lives if there's no contra indication and the biggest contra indication is non tuberculosis, mycobacterium co infection. If you give a patient a Zithromax in by itself and they have active mycobacterium avian complex disease, then they're going to develop macro wide resistant mac lung disease. So it is important to think about potential contraindications for these patients. Another might be cute ec prolongation or hearing loss and then consider the inhaled antibiotics if the macro slides don't help and there are there are a number of available ones, including inhaled october, my son inhaled as tree nm and inhaled Callisto. Um I don't think this is necessarily gospel in the sense that if I have a patient who has multiple or frequent exacerbations due to pseudomonas, I would certainly try the inhaled antibiotic prior to the macro lead, but the patient might still be a candidate for both approaches, regardless of which one you try first. So uh in terms of management summary airway clearance is first line always uh uh in terms of anti inflammatories, as I mentioned, I'm very cautious and rarely use inhaled corticosteroids. There's maintenance antibiotics for frequent exacerbate hours, including the inhaled antibiotics and MAC relied and of course targeted treatment for exacerbations. The therapies should not that should not be routinely used include routine inhaled cortical steroids, routine oral steroids, routine oral antibiotics and as I've emphasized MAC relied mono therapy in the presence of micro bacterial infections. The routine oral antibiotics are sometimes necessary in patients who fail other modalities, but it's extremely important to keep in mind that prolonged use of a single antibiotic will result in resistance to that antibiotic. Um and we've talked about this already patient education, you can't over emphasize it enough. And I do show patients their cT scans so that they have a mental image of what this looks like. You know, they can see dilated bronchial tubes in their lungs. I think they're also usually very savvy about what grows out their sputum. Especially now in the days of the patient portal, they are able to access their microbiology results which of course opens a whole other can of worms in terms of interactions with the patient, but it's all still necessary so that they understand their disease process airway clearance. Perhaps MAC relied as a new modulating agent and then finally antibiotics either for exacerbations or maintenance therapy. So there are some new therapeutics on the horizon, including neutrophils. The last days inhibitors which are very promising from a path a physiologic standpoint in that we would hope to break that vicious cycle chain early in the cycle by diminishing the impact of these neutrophils last cases. Um one of those is brings a cat in which I'm going to talk about in just a minute. Just a quick note about some other approaches. Our colleagues in great Britain use a fair amount more coolest in than we do and although it's not been studied well in the United States in great Britain, they have shown that cole Liston does reduce exacerbations in patients with pseudomonas in their sputum. Now colistin is available in the US. It's just not FDA approved, but I think it's a useful drug. I use it with some frequency because I do think it is effective, effective and safe. Certainly at least as safe as the other inhaled antibiotics. I want to talk just a minute about a new agent which is brings a cat. It is a DTP one inhibitor. It inhibits the activation of neutrophils. Syrian proteus is um it is an oral agent uh and this is a study that was published in the new England Journal of Medicine. Uh Just recently, it was a study of two doses of brains of kata versus placebo in bronchial patients. I'll show you the inclusion and exclusion criteria. Just a sec. So it was a 1 to 1 to one randomization. 25 mg of oxyCODONE, 10 mg of Brenda kateb and then placebo for 24 weeks with off treatment analysis for four weeks. The primary endpoint was the time to first bronchi exorcists. Exacerbation. Secondary endpoints was rate of exacerbations, changing quality of life respiratory symptoms change in post bronchodilator. FB one and change in neutrophils last day's activity, the key inclusion activity, we're adults with a bmi greater than 18.5 confirmed bronchitis ist able to produce sputum sputum color at screening and at least two documented bronchitis exacerbations in the last year exclusions were primary COPD or asthma diagnosis, hereditary or congenital causes of bronchi ex's current smokers, patients currently being treated for micro bacterial disease and presence of an acute infection that required antibiotics within four weeks screening. And I won't go through this in detail. But the point of it is that if you look at the three groups, the placebo and the two friends of captive groups, they are identical in terms of their demographics. It's not surprisingly uh female predominant, mostly non smokers. Um But as I say, the point here is not so much the detail is that the three groups were very evenly matched demographically. Uh huh. So uh in terms of the primary outcome, the top two lines are the two doses of brains a captive and the bottom purple line is the placebo. And what this shows is that Brent cotta prolong the time to the first exacerbation compared to placebo with both doses, both the 10 mg dose and the 25 mg dose with significant p values. It's interesting that the 10 mg dose was somewhat more highly significant in terms of the results than the 25 mg dose and I'm not sure there is a ready explanation for that yet. But nevertheless it does show that the 10 mg dose is at least and perhaps more effective than the 25 mg dose. Now the other the secondary outcomes was that the number of exacerbations was also significantly lower. With the two doses of brains. Academy. The percent of patients with more than one with one or more exacerbation was lower and severe exacerbations were half that of the placebo group and perhaps most important from a path a physiologic standpoint. There was a mean change in sputum neutrophils last's concentration greater with both brains Academy doses than with placebo. So the function of the drug in inhibiting the enzyme promoting the release of the Syrian proteus is was it was effective in reducing neutrophils, blasts concentration. In general the brains of Kedev was well tolerated adverse events were more common with the brains of kateb doses both of them than with placebo. But in general the 10 mg dose was better tolerated than the 25 mg dose. Both for the common adverse events like headache and dystonia and for the special interest adverse events such as hyper keratosis and periodontal disease. So in summary the brain's Academy met both primary and secondary outcomes. The primary outcome was prolonged time. The first exacerbation compared to placebo, there was lower frequency of exacerbations. Risk of exacerbations was approximately 40% lower than placebo. There was no significant change in F. E. V. One or respiratory symptom domain on the bronchitis questionnaire. I will say there was also no significant change in the tv one or respiratory symptom domain of the Q. O. L. B. Bronchitis. Ist questionnaire. Overall brands. Academy was well tolerated cough and Disney were more common in those who received runs a cat scan and dental events. Both adverse events of special interests were also more common with Friends. Academy. Uh it is it is currently being evaluated in a phase three randomized placebo controlled trial. So in conclusion therapies should be guideline based although our evidence based is still a little thin but they should even though our evidence base is still a little bit thin. But even with guideline based therapy we have to individualize our approach to each patient. I think it's important to keep in mind that reducing bacterial load is not the main goal. And we've emphasized this as we've gone through the talk improving patient symptoms and day to day quality of life is the real goal and also preventing disease progression. And we hope that by interrupting that vicious cycle that we've seen several times that we can in fact do that. Clinical trials are vital to these patients and any time you can enroll a patient in one of these trials that is extraordinarily important to do. So as we've mentioned, our evidence base is poor and the only way to improve it is to do more clinical trials. And lastly it is always critical to listen to our patients. They will tell you what's important and what works and what doesn't work obviously. And so hopefully as partners we're going to make progress I would add one point of context here is that bronchitis is maybe an ancient disease. It's always been associated with T. V. But uh it really hasn't had much in the way of attention until the mid to late 80s when chest CT scanning became widely available. So we're still pretty much in the infancy of managing these patients and hopefully things are going to improve. And I am encouraged by the number of studies being done now both in terms of natural history and interventions for bronchitis. Well let me thank you again uh for participating in this program and I wish you a good day. Published Created by
