Video Current Guidelines and Recommendations for Multimodal Management of Non-Cystic Fibrosis BronchiectasisA Year 2022-2023 Review Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Current Guidelines and Recommendations for Multimodal Management of Non-Cystic Fibrosis BronchiectasisA Year 2022-2023 Review Overview Good morning everybody. My name is David Campbell Har. I'm a clinical professor of medicine at N. Y. U. Langone health. I'm in the department of pulmonary critical care and sleep medicine and I'm the co director of the bronchi actresses and non tuberculosis mycobacterium program at N. Y. U. I've been in practice for approximately 40 years and I've been doing bronchitis is pretty much from from day one and maybe even a little bit before having trained at Bellevue and having seen lots of tuberculosis in old school. Um Michael bacterial infection and bronchitis is um uh we have a lot to talk about today. Um My only financial disclosures that I'm on the speaker's Bureau for instead that's not relevant to today's conversation. And as we often do, I'd like to start with a clinical history of a patient that I met approximately a year ago and continue to see at this present time, who I think represents a lot of what we have to talk about. The Gentleman is a 61 year old never smoker who presented for evaluation of chronic cough. Uh He provided a history of numerous childhood pneumonias in 1996. Um before his exposure of 9 11, of course was diagnosis having was diagnosed as having sarcoidosis. He was not clear about how that diagnosis was made. Uh and because of his 9 11 exposure has had pretty much yearly cat scans since uh since the mid um um two thousands. Um in 2019 he stated that for the first time, Michael bacterium. Avian was isolated and he was treated with 18 months of three times a week guideline based anti non tuberculosis um antibiotics. In 2021 he was stopped and uh liposome OMG cason was initiated as monotherapy without sensitivity having been done and he stopped his um nebulizer uh me cason before he met me because of worsening cough which was his chief complaint. He exercises regularly and uses a vest for airway clearance. Uh He did not describe gastroesophageal reflux, trouble swallowing, but particularly in questioning noted that he cleared his throat a lot and had a a wet voice at all times, which people noted. His physical examination was essentially unremarkable, with a well developed and gentleman with scattered crackles and otherwise clear examination, a chest ct which was provided to me by the patient revealed um um um right middle lobe, um significant bronchial basis as well as compaction, partial collapse of the right middle lobe and scattered areas of bronchi excesses throughout the visualized lung fields that are here predominantly um um cylindrical with some areas of perhaps vara coid or pre uh pre cystic bronchi exorcists in the right middle lobe interior lee. Um Similarly in another lung field higher up we see pretty much the same thing with scattered areas of new court imp action. And if you look at the left um left mid view, left mid lung field. On this view, you see that this is a high attenuation area suggestive of aspergillus inspiration, lo and behold three or three sputum cultures. Grew mycobacterium a. V. Um three of three as well grew aspergillus from a goddess and the Calgary staphylococcus aureus of a sensitive strain. His evaluation was done and we'll talk about the evaluation of patients. He had multilevel dysfunction of swallow with pooling of secretions in the area around his voice box and above his above his Gladys with occasional penetration. We'll talk about the importance of that as we go. His immunoglobulin levels were normal alpha one anti trips and was normal. And he had therapeutic anti pneumococcal antibody levels. So demonstrating that he clearly was able to use his immunoglobulin levels for a good purpose. His immunoglobulin e was significantly elevated at 27 87 with normal less than 2 14. And similarly had a peripherally assign ophelia of 770 with normal less than 400 pulmonary function Studies which I'm not gonna review the tracings revealed only mild obstructive dysfunction with significant bronchodilator response in this revealing um indicating significant inflammation. So in some these multifocal bronchi ethicists uh and we'll talk about how he might have gotten it with significant multiple co infect ear's uh in this, in this individual. So we all see this patient. Um many findings, many parts of the story, many possible ideologies and many organisms to deal with. And we have to figure out what it all means and how to make sense of it. I'd like over the course of our next time together to make this kind of a survey course in bronchial basis uh updated to today and maybe even a couple of weeks from now. I realize as we've, as I've done before trying to address both basics and advanced concepts for people who know more about it. Um and people who really are just dipping their toes into this area, which is so important, ambitious assigned with a lot to cover and hopefully I'll leave you with nothing else with food for thought. I think the modern age of bronchial basis if you wish, started in 2002, a watershed article by Alan barker um who continues to be a shining light in the area bronchi ethicist opens with the statement that bronchitis is an uncommon disease orphan an orphan disease. As it's often called. Meeting less than 200,000 individuals with this disease with potential. This is quoting for barker potential for devastating disease, including repeated infections requiring repeated antibiotics, Disabling productive cough, Disney and occasional hypothesis. So there's a clinical definition there. I remember when I was training, they told us not to ask if a patient produces sputum with bronchi exorcist, but how many cups full of sputum and how many boxes of tissues they used a day. So that's the old school, very wet bronchi exorcists or clinical definition The neck in the early 1800s um provided thought about separate of flim. So uh conversation about the infection and countries bronc ah graffiti initiated in 1922 is the radiology of bronchi ethicists. Lynne reed in the 19 fifties um defined histology uh indicating that there was a unique anatomy um in fact separating this from what other people considered to be chronic bronchitis and other causes of coughing sputum. Now, with all these areas of recognition and with the decline in tuberculosis, pertussis and measles, uh effective antibiotics and vaccination. Um and uh consciousness raising for bronchi ethicists, logical expectation is that bronchi ethicists and it's important clinical parameters should be on the decline. But and again, another very important study. This is um from a paper in 2004, but this this graph could be repeated again and again with unfortunately no significant change in what it shows an increase in the rate per 100,000 of patients with clinically relevant bronchi ethicist. This is based on reported by physicians is clinically relevant. You see that with every decade. It increases from three And five respectively for men and women uh in young adults all the way up to individuals over 75 uh women where more than men of many, many, many times more than that. Um and what we could see that bronchitis is now is well over 200,000 adults living in the United States. Most patients are over 65. So it certainly is no longer an orphan disease or a rare disease. So we have to figure out what this means. Is this unique to the United States? Certainly not. Uh in defining bronchitis is the true prevalence is hard to discern because there are too many variables. Um how are you defining it? Um who is defining? It certainly seems to be um defined that a higher prevalence in developing countries less to medical care and the french series. In 2012 2.6% of respiratory patients had confirmed Rocky exorcists in the United Kingdom mortality was 3% per year report in 2010 United States. Hospitalizations increased in the same nine year period up to 2010. And the steepest increase in the age of 65 was the NIH study uh showed that 8.7% per year increase in the year 1997 and 2007. So why is the increase? Is that there's actually more disease perhaps because the the aging population or is it better detection As always? And as always, we always consider some of the above. Um as the world starting to explore this in china, the prevalence increased by 2.2 fold between 2013 and 17 in Germany, they diagnosed over 17,000 cases in 2013, which is 21/21 per 100,000 half of whom were males. They have a little bit distribution. And in italy um that 50 cases per 102,230 for 102,015. So age um seems to be a very important role and depending on which population you look at. It seems that populations that look at C. O. P. D. As you see all the way at the bottom of the slide will have more men than women if you keep it pure non COPD Gronke exorcist, we'll talk about that overlap later. Uh It seems to be women way more than men. So there's a great economic burden to this addition to the human cost. There's a big dollar cost. Hospitalization is the most expensive part of all this proposition with pseudomonas hospitalizations being the tippy top of the iceberg for all of this. So we have to address the human cost cost of course which is significant. And bottom line unfortunately is the dollar cost as well. Uh In response to this. In order to investigate this, the United States launched the U. S. B. R. R. R. United States bronchi X. Research registry and the european bronchi excess registry called Embark and uh separately and together which they now work together very closely and we're very fortunate N. Y. U. Langone to be uh an integral part of that part of that group Um with a significant number of significant percentage of their of their um study patients. So they launched 27 objectives of six priority areas to improve treatment and decrease exacerbations, improve treatment of exacerbations when they happen and better treating infection, improve health care, quality related quality of life, identify predictors of a poor prognosis, understand the impact of the conditions and conduct patient centered trials and once more again we should be talking about many of these going forward. So the first thing if you want to talk about a topic, as I said, you have to define it. If you don't define it, you don't know what you're measuring, you don't know what you're prevalence is and most important, you don't know how to address the problems. So in the Lancet article, Lancet rest between medicine recently is 20-2 earlier this year. They made their definitions. So everybody be talking the same language. It's both the name of the disease as well as a specific radiographic appearance that may or may not be associated with disease. And that last caveat is very important. Asymptomatic patients with bronchial basis bronchi exorcist, maybe a feature of numerous other clinical entities including cystic fibrosis and today we're focusing on non cf bronchi exorcist COPD, asthma, interstitial lung disease with traction bronchi ethicists and post infectious tuberculosis, other infections. So it's a great potpourri of, of causes of how we get to this topic. Radiologic bronchi exorcist has been documented and up to 20% of healthy adults over the age of 65. What to do about that that can help us and shouldn't be paying attention and because of the variety of associated disease entities and there is a lack of consensus regarding treatable traits. So does it really matter how you got to your bronchi excesses or there are things in common that we should be addressing the subjective nature of radiographic findings including definition. All these need to be addressed and that's what embarked and the U. S. B. R. R. R. Doing sharing data together. So let's unpack that last slide. There's a whole lot there and if we get the definition right we have a much better chance of understanding that these are the patients. I just want to come back to this issue of undiagnosed patients of asymptomatic patients in the study of South Korea. In the middle of the slide they looked at patients over the years 2016 and 17 who had CTS for all reasons. 27 a half 1000 patients were screened. 1000 5 had brought the exorcist on CT which adds up to over 2000 per 100,000 prevalence. There were more asymptomatic patients and symptomatic patients with female a female sex older age C. O. P. D. And low F. U. V. One being the factors that are related. So should we be paying attention to patients who have a symptomatic disease? If we hope to keep them out of trouble. So let's let's emphasize the clinical definition in the middle of the page and they got 74 articles reviewed and this was studied by an International Consensus Committee and they define Bronchi actors clinically as a chronic respiratory disease multiple causes associated with different conditions. And although in many patients of course cannot be identified, the diagnosis is clinically significant parenthesis disease requires both clinical and radiographic criteria. So we're all anxious. All the people watching this webex zoom are anxious to to get into it and diagnose it. But if you don't if you over diagnose it you may be doing just as much the service to the patient and studies as as under diagnosing it. Um So confirmation of the presence of on C. T. Requires conformity clinically the core symptoms defined by James Chalmers, one of the three directors of of embark uh and and a shining light in the in the field of research um In in bronchial basis. Core symptoms of course sputum production dispute, exertion. The current pneumonia, lung infections and people called bronchitis and asthma or COPD unresponsive the usual treatment. So when somebody has asthma COPD or so it seems not responding not an obvious cause. Maybe you got the diagnosis from or maybe you should be digging deeper and looking at bronchi exorcist and getting a cat scan. Additionally associated rhinosinusitis chest discomfort, fatigue and weight loss for really sick patients, repeated isolation of h flu staph and pseudomonas, why does this patient have this organism? And then certainly others you know sorry sha uh and and the like why why does somebody have this it should make you think and findings associated with the other conditions that we're gonna be talking about. Um When you look at primary causes. This list is similar to a list published by an O'donnell um from Georgetown uh approximately a decade and a half ago. It's kind of the same list although different different members of the list kind of slide up previous infection as you see. Uh And an idiopathic used to be number one and now um idiopathic is one. We're now looking at childhood wet cough. A lot of this may have started way younger. Um But we didn't recognize it. So maybe some of these idiopathic people are people who actually had the beginnings of it when they were kids. And with the people who always all the way over on the left side of that prevalence stage slide that I showed all the way back at the beginning. So you can think of it that somebody had some of it early on and it progressed as they got older. Previous infection bacterial or viral. You think of that more often in people of localized disease aspiration uh and swallow problems again rising higher and higher on the list. And certainly we at N. Y. U. Favor that as an important thing to look at hypoglycemia. I. G. G. Deficiency. Nice to diagnose because you can replace that primary serial Salieri dysfunction. Very hard to diagnose. They're using exhaled nitric oxide. But most people are not gonna be diagnosed with that. So it's way under diagnosed, probably connective tissue disorders. And then co morbidity COPD asthma, um inflammatory bowel disease, um rheumatoid arthritis and alike. Um So it's because of cat scan capability and accessibility that we become aware of the increased prevalence. So let's let's be very specific about the cT findings. So again be specific 2020 review in the Netherlands in Italy 5000 papers to find and validate what's the definition of bronchi excesses radia graphically. And they pick three. Number one pulmonary artery diameter larger than the Luminal diameter of the corresponding airway. Now again, if you're looking at the long base and somebody didn't take a deep breath that may be thrown off. So you're better off looking at the mid long field, upper lung field if you can find it. And again, there's a lot of debate about, is it the internal diameter? The external diameter. But we'll keep it simple for now. Uh Number one, a lack of tapering of the airways as they extend toward the periphery. Uh And again you have to remember that central bronchi exorcist as well and finally visible airways within the most peripheral one centimeter of the law. So accessory findings, bronchi wall thickening, mucus plug entry and blood smaller with diseases in ct. Now again, if you see going back to a visible airway within the most peripheral one centimeter. Are we going to make a diagnosis based on two of those. And is that important? Uh These are things that all need to be worked out that somebody is still one is gonna go on later classification. Um um In addition to being a way of identifying helps us think about the likely of the likelihood that somebody is going to be sick and the degree of dysfunction all the way on the bottom. So as you move from cylindrical, which will show you a minute. With the bronchi rules are smooth, barrack, oid with their regular and secular. We really lose all definition. So cylindrical on the left, the Bronx, the airways are dilated um as you can see but again the the the walls of them are relatively smooth that may progress to Varick oil or varicose with focal constrictions, little bumps, further weakening of the wall and finally Cingular cystic, which is the most severe. And it's just an area. Obviously coexists with, with less with less severe on the same side but there's just gonna be puddles of mucus may collect their um it's certainly going to be very hard to do every clearance there and it's certainly going to be very hard to get antibiotics into those areas um to treat them if there's infection. Um So uh further in addition to the shape of it. Um If you have localized disease, it may be post inflammatory and may be less likely to be clinically significant. On the other hand, if it's diffuse you think about some underlying disease more likely clinically significant. So again a combination on the bottom a combination of the degree and the extent implies the expected morbidity. Um um Though certainly things may progress the distribution. We know everybody who follows this um in motile cilia um And non tuberculosis mycobacterium particularly the right middle of singular lady Windermere syndrome. Lower lung fields. Um U. I. P. N. S. I. P. Chronic aspiration um um Central lung fields, allergic broncho, pulmonary aspergillus and chronic hypersensitivity pneumonitis and finally upper lung field. Favorite sarcoidosis and progressiveness of fibrosis of silicosis. So you kind of keep your wits about you. And as you're looking at the cat scan you want to see if it can direct you into things about both managing the patient and and going one step deeper in terms of trying to find the course. If you find the cause like alpha one you may be able to replace it. You know the globulin deficiency certainly replace it. Um And um cystic fibrosis there are new replacements for the missing enzymes and genetic deficiency. As the airways become weaker, the cough becomes less efficient and the cough the pressure behind the cough is ineffective and instead of pushing the secretions forward to get them up and out. Uh It moves laterally to the wall of the airway and it loses its effectiveness. So what is the effect of age on bronchitis is so once again I want to show this this slide. You can I can show you a slide and updated slide I like this one comes pretty I've been using it for years but it hasn't changed as you get older more than men in the United States because you exclude COPD are more likely to have it and they're way more likely to have it than when they. So uh lung function we'll talk about briefly. Uh So they followed patients over the age of 70 half of half of the more male. And they noted that the F. E F. E. V 13 lines down the slide declined by 52 mls per year instead of the expected 30 mls per year. Uh And they're more likely to decline if they're pseudomonas patients more frequent exacerbations and more significant inflammation. This was not affected by bronchodilators, inhaled topical, inhaled cortical steroids, chest therapy or even intermittent prophylactic antibiotics which really is not used very much or maintenance, which is not used very much at all either. Uh So if bronchial basis is untamed and maybe even if it is there is a greater than expected loss rate of loss of lung function. So so how does this all happen? How do you go from the young patient with less likely to have bronchi X. Is two more likely bronchi exorcist. So a decade or so ago, cole published what became known as cole's vicious cycle hypothesis stating that if you start at the upper left, if you have bacterial infection and colonization you have neutrophils inflammation of the airways. And if you don't clear the bacteria and you similarly don't clear the neutrophils as they degrade in the in the airway. Then the cytokines and other materials in the white cell designed to kill the organisms within them are also damaging the airway. So you have more airway destruction, moving down to the lower right and distortion. More more, more abnormal mucus collection because if the cilia don't work then you can clear the airways and it becomes a vicious cycle more recently uh published has been the concept of what's called the vicious vortex. And you see that these four poles of the problem uh kinda interact with each other and it's not simply going around in a circle but it's going in every direction. And we're gonna talk about each one of these on top is epithelial dysfunction and mucus hyper secretion sillier dysfunction. So you can go to the mucus moving down to the to the pink slide the inflammatory process with neutrophils and T cells moving down to the bottom of the green chronic infection and bacterial virulence factors and finally lung destruction in the great so let's kind of do one at a time starting with bronchi ecosystem lung tissue destruction. So we know that bronchi excesses is characterized by this cycle with progressive airway injury as we talked about irreversible bronchial dilatation uh injury as it happens. And finally chronic infection with pseudomonas. Mtm and Demopoulos can cause further airway damage. So you know talk about N. T. M. Which is not a talk for today but there's always the chicken egg slider which causes which. So if you have damaged their ways of getting on tuberculosis micro bacteria and if you have non tuberculosis mycobacterium causes more damage. And we'll talk about how pseudomonas does that as well. Um So it becomes you know that vicious cycle vicious vortex um mucus hyper secretion and Salieri dysfunction. So you you can clear your airways. So what what do we know about and what can we do about that? Well airway clearance has been a mainstay of therapy since forever. Um But you know now we're trying to understand why we do what we do rather than we do it because we do it. So let's keep doing it. So the logic is that if you have a mechanical problem because you lose cilia dysfunction. So let's try a mechanical solution which is airway clearance. Let's try to remove dispute. Better get the mucus Salieri transport system compensated for because it's broke broke in. Uh So airway clearance seems to be more effective in coughing in these patients. And it's recommended by the international guidelines um Different methods. Um And again, you know this is its own its own talk active cycle of breathing huff cough which is coughing with your Gladys open instead of closed postural drainage on the right side oscillate story devices as they call them. Um You know, going back to the flutter valve, lung flu acapella and the arabica, all of which um cause vibration and that vibration is to simulate what happens in your, in your airways to clear secretions. Uh, aerobic is kind of the coin of the realm right now. That's the most favorite. Um We'll talk about nebulas, solutions and obviously percussion that you need somebody to help you with it some people use because of devices, but as we'll see, there's really no one size fits all. And I think that's the most important thing to remember. You have to be willing to try more than one thing if the first one either doesn't work for the patient or the patient really can't do it are tolerated. The observatory devices are inexpensive, um, you know, $50, Easy to use. Take up no space. Uh they last kind of indefinitely. They're portable. They don't last forever. Just like your toothbrush doesn't last forever every once in a while you have to get another one. So they they they provide frequencies of 15 to 29 hertz for flutter a little bit more for the acapella and healthy lung cilia beat between 11 and 13 her. So if you can compensate for the Salieri beating that of the silly that don't work. Try to try to create that same trachea mucous clearance by using a mechanical as it's called a circulatory device and emphasize the patients that the vibration that's caused by their exhalation is what's doing the work. There is a vest which is exactly that a patient wears a vest. Uh It enhances sillier beat frequency thins the mucus. Um. Um And some people find it very helpful. Some people find it not helpful. My experience is that unless somebody has lots of secretions that's very thick and can't be moved. I always prefer doing airway clearance and you kind of do airway clearance and depositions lying on right side line on left side, sitting up with some health costs in between. But again patients need to be coached. Um And um you often want to add hyper tonic sailing. Um In 2012 blinded randomized study of 12 months using 6% Saline United States we have 3 3.5 and seven. And they compared that to normal saline every 12 hours quality of life improved by multiple measures in Saint George and the livestock off quotient Questionnaire sorry. And they found on the bottom of the slide that 55% of patients with hypertrophic saline had positive cultures. The start of therapy and 15% um had positive culture at the end of the study. So it clears secretions and cleanly gets clean. So if you decrease the bacterial load you'll have fewer fewer bacteria present if you count them in a culture and you're less likely to get infection. Um hyaluronic acid has been added uh in some studies lately to this hyper tonic saline and cystic fibrosis patients to improve the tolerable. Itty some patients find the hypersonic saline too irritating and decrease airway hyper irritability and the salty flavor. In two studies, it appears to have the same patients have the same effect that non cf bronchi actresses as in cf bronchial versus it's not yet ready for prime time, but it's something that keeps coming up in the conversation. So something to keep an eye on. It may be adapted soon. Um so the biggest problem is adherence to therapy doc I just don't have the time. I I do it a couple of times a week, I can't do it twice a day, seven days a week, ages drunk, predictor of non adherence. Um multiplicity of medications, I'm doing so many things, I gotta take so many medicines and first I have to use the albuterol, then I have to use the hypothermic sailing, then I gotta use the aerobic and I got to do it twice a day and it's too much. So if you explain to patients what it's all about the middle of the slide, Non understanding of the way clearance benefit is very important because again it's it's annoying. It's a lot to do. So the role of airway clearance is to be emphasized by the physician by the psychiatrist by um just physical therapist and again there is no one size fits all, but this is becoming more and more accepted and you need to understand yourself. So take the time uh there's a bronchi actresses toolbox website from Australia bronchi exorcist toolbox that has lots and lots of different things that patients and watching you can watch. What about physical therapy and the story of physical exercise. So it shows that the in 2018 it seems to promote airway clearance, decrease inflammation, improve quality of life and non cystic fibrosis bronchial emphasis um the exercise itself especially what they call cardio, you know do the treadmill, do the bike go for a brisk walk Now this is parallel to but separate from the benefits of chess bt. The mechanism is to be determined. It seems to work. But when you ask exactly why you know the patients who want to know patients want and we don't know exactly why but it does work. Let's talk a little bit about biofilm which is is certainly important and understanding evolution of disease and and possibly the benefit of chess therapy. So we know that when bacteria are floating in water are flowing in water and they come across all the way up to the first panel on the left um as they flow across a surface certain bacteria which are biofilm formers attached to that surface in a matter of seconds to minutes and they build up and within minutes to hours from what looks like the panel on the in the middle where this grows and forms these complex structures and these bacteria in there and they're protected from everything around them. Their rate of growth slows their need for oxygen decreases. The need for nourish nutrition decreases the ability for antibiotics to get into those areas decreases. So they're living in a protected environment. And then as it continues to grow and on the right and get too big to sustain itself. Pieces break off it disperses and all these little fragments go back again and attach again. So in damaged airways we know that biofilm is something that is how bacteria grow and certain organisms are bacterial biofilm favorites such as pseudomonas again, aspergillus again and michael bacteria again. The co conspirators, the co conspirators and the bronchi ethicists. So biofilm can be formed by a single organism by multiple organisms together like pseudomonas and sip a Shia together can join up because one attracts the other. It could be different species such as staph and pseudomonas or staff in Sarasota. Um And it can be different types of organisms. Different taxonomic levels of mycobacterium pseudomonas, mycobacterium aspergillus. So these, when you have biofilm and by definition all bronchial asthmatic airways have biofilm. All cavities have biofilm so you have to address that and we're trying to figure out how to deal with the biofilm problem. So as we talked about the impaired fake aside function, the substance inside the biofilm causes death of the white cell. Uh and then the white cell, death of the white cell again causes further damage. So this biofilm may be part of this vicious cycle vicious vortex and bronchi. Exegesis of how infection together as we see infection all the way on the bottom panel um causes further tissue damage on the gray box on the left. So that's how the lines do in every different direction. Let's talk about chronic infection. So cycles of airway infection and chronic infection with these particular organisms is associated with airway damage. So what can we do about it? So the microbiome, we know the lower airway is not sterile in health but in a continuous state of maintaining homeostasis. Just as your skin has certain bacteria that normally they're your sinuses and those every area of you or a patient um that is exposed to the outside world has a normal group of bacteria that are present in a particular distribution it's expected. So non microbiological analysis of respiratory secretions by PcR is a more is more sensitive in assessing human microbiome. And in bronchi ethicist the microbiome is disturbed. That's one of the keys of understanding bronchi ethicists. So in respiratory disease and exacerbation the microbiome is further disturbed. So you look at this panel uh starting all the way on the left. If you look at um in this particular patient you see the first panel all the way on the left, you see a great diversity in each color represents another organism that's president, we know once you start using non culture techniques, non microbiological techniques and use pcR instead, you find that there are 1,000,000 organisms that our president not usually 2030 40 50 that we think of like staph and strep and pseudomonas klebsiella. So you see that there's a certain distribution as president of the airway. Lots and lots of colors and lots and lots of different panels. And if you look at this individual who is sick and you look at the oral sampling, you find that there is still some disruption of distribution dispute um is less disrupted. And if you do a bronchoscopy where you selectively analyze what's going on in the normal and the spared lung in somebody with pneumonia. And comparing what's the affected lung despaired lung continues to have the dive diversity and the affected lung loses diversity. So the light green panel has become much much bigger and overtaken it. And if you compare it to the how how big the light green panel is in the affected lung compared to the spare lung um um It certainly is quite disturbed. Now this helps us understand why is it when somebody is sick and you send over sputum culture and it comes back with normal flora and you don't understand the patient understanding and say, well it's the same organisms but they're just present in a very very different distribution. Normal cultures that you send to a lab whether it's a hospital and a commercial lab they're not gonna you know, they're not going to give you an exact distribution when it comes to normal flora. They may tell you there's a lot of staff or a lot of strep uh sorry a lot of pseudomonas, a lot of Klebsiella, copious scanned etcetera. But they're not going to give you uh distribution like this. So disruption of the normal diversity is the key to understanding bronchi axis and stable patients. And certainly a key to understanding and unstable patients who have an exacerbation. So the greater the loss of diversity in a patient with bronchial basis, the more severe the bronchi ethicists. Certainly if you alter the microbiome, this potentially eight's other infections which we all know like non tuberculosis micro bacteria. We know that this is promoted by swallowing problems and Asafa geo problems. Because you're introducing oral flora into the upper airway. Um And to some degree even if it penetrates the lower airway. But we used to think of if the patient is not quote aspirating unquote meaning materials not getting all the way down into the lower airway. Um Well that's not important. Well there's plenty important because if you soil the upper airway and disrupt the microbiome. You're allowing different organisms to take over different organisms that are not in check anymore. Um And different organisms that can further uh allow patients to be have exacerbations. So future management may be customized with the microbiome like a microbiome transplant. Just like we do fecal transplants. We now maybe doing sputum transplants, pardon me for this morning conversation. But that may be going on and certainly treating patients repeatedly for lengthy periods of time with potent antibiotics, affects the microbiome. So what can we do about that? So, you know, again, we've been using inhaled antibiotics, inhaled antibiotics and non cystic fibrosis Frankie. Exorcist was reviewed uh in a recent article in 2022 they looked at 10 years of studies, a literature review from multiple search engines. They looked at over 31,000 articles, believe it or not that takes a lot of sitting power. Um and 1362 were actually screened and then they took the final eight. So they looked at antibiotics and hailed antibiotics as adjuvant and follow up treatment. And the most current, the most common course was 28-30 days on 28-30 days off. And as most of us who use it. No, but again, you have to study it to really know it fewer systemic side effects were present. And nebulizer antibiotics. Then in systemic beit oral B it intravenous. The local irritation is often reported by patients but those can most often be obviated the sore throat, the irritation up railway pre medicate with the nebulizer bronchodilator. Um have the patient's gargle uh glycerin and so on. And they will tolerate the nebulizer antibiotics better to bring my son is the one that's approved by insurance companies for facist IQ fibrosis, gentamicin is plenty good. Emi cason, we've gotten more used to using it because of um non tuberculosis michael bacteria, a liposome. All ciprofloxacin which was promote which was proposed but did not get FDA approval as far as I know is that the state encased in as tree mm. Lots of nebulizer antibiotics have been tried and again, the clinical uses most often limited by insurance coverage for non cf patients. So I find that gentamicin is much less expensive, easy to work with. Um does just about the same thing as Tober mission in terms of grand gram negatives and it's less expensive and we can get it, we can get by with that. Um Now, pseudomonas colonization we notice is a very significant influence on the lung microbiome and the non effect. Noninfectious effects of pseudomonas may allow for stratification of patients with non cystic fibrosis bronchi excesses. So even patients who are not having exacerbations at any given time with their Bronx pseudomonas if they carry pseudomonas in their sputum and we can quantify that. Perhaps we can understand which page are at greater risk for decline in their bronchi exegesis over time. So precision medicine as they now call it. These measures may be devised depending on the and the phenotype of the patient or in other words, some patients with the same cat scan will do better. Others will do worse. And you have to try to figure out how to how to stratify these patients in terms of what to do to keep them going for longer. So again, in addition to combine systemic and topical antibiotics. So now the newest area for research and I want to spend some time dealing with three different considerations Neutra filic inflammation um um in patients with bronchial excesses which which really seems to be the great hope going forward of many because of its tremendously damaging effects. So until relatively recently, chronic mackerel and therapy with azithromycin was the only treatment for bronchial basis that was supported with high quality evidence. And um certainly we know that patients even with pseudomonas which obviously is not sensitive to to to mackerel AIDS patients did very well. The mechanism of action is not completely certain. Uh and but but it does work in patients using Three times a week, 500 mg of azithromycin. Um but again, we will get skittish because those of us that see lots of non tuberculosis mycobacterium, particularly in cystic fibrosis. The last thing you want to do is uh is risk acquisition of resistance. So patients uses the remission, please make sure that you're screening for non tuberculosis mycobacterium on a regular basis. So looking for other agents of inflammation that that we may be able to manipulate contestants. E inhibitors as anti inflammatory agents. So an article in the european Journal of medicinal chemistry in 2021 discusses contestants see as a license. Almost 16 proteus and again, I'm a clinician. So so you know, we'll do our best to understand this together which mediates the maturation process of of polymorphic nuclear Lucas, sites of white cells, the organism, the cells in the in the airway, which can cause damage. So Kotex and C is a potential target for treating inflammatory diseases, not just bronchi ethicists, inflammatory bowel disease and the like so pharmacologic intervention with inhibition of the pep to deal two days one DPP one is being studied and patients were clinically complicated bronchi ethicist to see if we can get our way into that cycle and prevent an interfere with neutrophils production. So charmers published again, uh you know, as Chalmers does a watershed article on a medication called Brent Mcadam, which is a DPP one inhibitor and bronchi ethicists. And they did a 24 week trial in 2256 patients who had at least two exacerbations of bronchitis a year. And that was done initially as the willow trial. That's now being extended uh within the aspen study. And they looked at time to first exacerbation, which is the primary endpoint and the rate of exacerbation, the secondary endpoint in this sputum neutrophils activity and safety were assessed. So if you were taking this medication and you were given those of zero mg, 10 or 15 mg of it. Um what was affected the most important thing being. Did you decrease the time between the time you started the medication? To your first exacerbation and if you had one was wasn't milder. So in the in the placebo was 67 days. And then the different study groups that was either 90 634 days. So it seems to have a pretty pretty demonstrable. And they noticed that sputum neutrophils lastex decrease. So you could show that it did this by decreasing neutrophils activity and the incidence of side effects which they found dental and skin side effects was higher. Uh But not intolerable. Um well tolerated patients who took the medication. So the conclusion in the phase two study which was the willow study DPP inhibitor is safe and effective in patients with bronchial actresses in preventing exacerbations. Now this is this gets a little a little uh little fancy. Um One of the people who works closely with dr Chalmers. Um Doctor care and Lancet in 2021 talked about any T. Formation neutral, fill extra cellular traps. It's an active process with neutrophils extrude a mesh work of extra cellular fibers. Sorry about the duplication and this is a picture of it. So this is a neutrophils cartoon with all these fibers looking a squid like a squid. And these fibers are composed of D. N. A. And his stones with bacteria sidle proteins to immobilize and disarm pathogens? Well sounds like a good thing to have around but they found that that these proteins also are mediators of inflammation. And these mediators of inflammation can worsen bronchi ethicists. So they you know the double edged sword. So they we know it has been discovered that people with a rare genetic disorder that can't make these nets even though they don't have these any T. S. They can still kill bacteria. So can we kill bacteria with with without the downside of the N. E. T. That may cause damage to the airway and still take care of the infection. And it's been found that in the orange in the middle proteins derived from the N. E. T. S. Are associated with severe disease and bronchi excesses and worse outcomes in those patients. So bacteria such pseudomonas and Hemophilus which are resistant to being killed by the N. E. T. S. And escaped the action of antibiotics and neutral film neutralization. So these are problem bacteria. Mackerel loads were successful in reducing airway any T. S. Without lowing white sale numbers in the air waste. So there are lots of ways that we can manipulate this. So reduction in any T. S. With systemic antibiotics and mackerel AIDS is associated with favorable clinical results. Get rid of the N. E. T. S. Right? So these are the traps and this is the little cartoon. And you see in the bottom panel um that there are lots of different considerations for this uh the inflammation of atherosclerosis that ends up with plaque on the bottom of panel B lung disease, including fibrosis uh interference with the different uh lines of the bloodlines and finally the beneficial effects uh from this resolution and so on. So we have to figure out, you know, these N. N. T. N. E. T. S. Are there for a purpose, but how do we balance getting rid of with with with the benefit? So in terms of trying to stratify in further investigation of inflammation, they came across this new uh protein in airways called pregnancy zone protein PCP. And this is the third aspect that I wanted to talk about the first um accolades, then Bruns, academy nets and finances pregnant zone pregnancy zone PCP PCP. And this is exciting in airways of patients with severe bronchi axis and pseudomonas. And they identified it initially. And the reason it's called pregnancy zone is because its president in the serum of women. So it's a T cell immunosuppressant to prevent rejection of the fetus because that's an al a graph that you know, it's not part of the patient's body during pregnancy. So they found that elevate levels of PCP are associated with disease severity and frequent exacerbations and airway infections. Again, let's see how we can use this to help us understand. It was found in the cytoplasm, the neutrophils was released during the acute inflammation. It's associated with the traps and the confirmation of role in the N. E. T. S. And path of physiology of rocky ethicist goes around again to include PCP. So it also may explain what pseudomonas is a poor prognostic factor because it increases traps increases PCP. So uh it's associated with lots of different organisms. A busy slide apologies including marcella Demopoulos and others. Uh PCP is linked to frequent exacerbation during these neutral filic inflammations released during the regulation. Uh It's essential to the pathogenesis of the disease. So it may be the first link between chronic Neutra filic inflammation and impaired host immunity. And it correlates with bacterial load response to antibiotics when it drops low levels of COPD. Two separate bronchi emphasis from COPD um in terms of management and finally uh very important quantifying this this protein may allow selection of high risk net driven bronchi excess phenotype in terms of intervention. So here we are given its known immuno suppressive effects. PCP maybe the link. So if we go on our on our vicious vortex, we see that the arrows go back and forth between infection um and Neutra filic inflammation and tissue destruction. Um and so on. So this this we understand why pseudomonas has a negative factor and and all of this can be manipulated. I wanted to talk about the recent recognition and this will be the last section of the talk. But it's important. So they they note that bronchi ethicists and other entities. We see it together with COPD. So they got together a group of experts from several countries from europe Turkey and Israel. It's a lot of countries defining c COPD specifically as persistent respiratory infection. Again, not do the bronchi excesses and also bronchi excesses defined classically. And they found that that somewhere between four and 75% of patients had a combination of these depending on how careful you are. Um So it's important to separate because there are more COPD that they have more shortness of breath and bronchi excesses, more infections. So something to keep an eye. And they said, well, how do we, how do we crisp down this? They suggested the pneumonic of rose. So radiologic, we talked about how you define bronchitis is radio graphically obstruction. How you define COPD physiologically the symptoms to a more cough expectorant in fatigue plus exposure. So if you're a cigarette smoker think about COPD, other toxic exposures. Think of COPD. If you didn't think about it, think of primarily um um bronchial basis. So again, you want to be crisp about how to manage it. This association with chronic rhinosinusitis. If you consider what's called the unified airway where it's not the upper airway and the lower airway sinuses are separated from your chest. So we know that crs chronic rhinosinusitis with asthma has been associated and particularly nasal polyps, they did a prospective study putting it together with high resolution studies and they found that 7200 and 40 76 patients were 41% of patients with asthma and chronic rhinosinusitis were found to have bronchi ethicists so that the people who had chronic rhinosinusitis with their bronchi ethicists had more exacerbations, lower FTV one gregarious NFL counts and more severe bronchi exorcist. So manipulation of the sinuses. Again an important area to consider. Uh listen, ophelia seems to be another way that you get inflammation and bronchial basis. Uh this has been studied in spain uh by several of the, of the embarked people as well as by a liberty and italy emphasis in the vicious vortex model. The emphasis has been on neutral filic inflammation. Um in COPD we found that people who have high risk NFL counts respond better than held steroids. So if you can correlate um uh in your fourth bullet point bloodiest in affiliate, less severe bronchi exercise phenotype. So uh all the way at the bottom we know that if you have a higher threshold you have mild, higher number of the NFL's milder disease, better outcomes, fewer high hospitalizations and better lung function. So again, in terms of stratify ng in terms of who to watch and how this may help us last association, although we didn't deal with inflammatory bowel disease as an association. Again, a very current article about the association with rheumatoid arthritis. So we always think of uh in fact of interstitial lung disease from rheumatoid arthritis as causing traction bronchi access there, patients who had bronchi excesses without interstitial lung disease. And again they found that 100 and 23,000 patients between 2010 and 2021 had rheumatoid arthritis and they matched them for patients from everything else. And they found 57 cases of isolated rheumatoid arthritis bronchitis is in 360 controls without rheumatoid lung disease. If you had zero positivity and older age at your time of diagnosis and a lower B. M. I. You're more likely to have bronchi emphasis with your rheumatoid arthritis. Um So if you have chronic inflammation going on in your in your joints or in your lung. The question is which which comes first, which is the which is the prime mover in which is the secondary autoimmune phenomenon. So patients with positive CCP antibodies and no R. A. Have a higher incidence of bronchi exorcist. So if you have a patient like that, think about bronchi exorcist, you know for patients coughing um we talked about pseudomonas with a specific infections, non tuberculosis michael bacteria, non tuberculosis michael bacteria um live thrive in in biofilm. Uh and biofilm may be in the bottom of the slide the airway deficiency that allows michael bacteria to take home. We always say that everybody's exposed to, it's in everybody's water, everybody goes in the hot tub? Everybody goes in the steam room, Everybody goes in the jacuzzi. So why do some people get michael bacteria infection and most people don't. The answer is if you have biofilm in your airway already because you have bronchitis is the micro bacteria take hold. And michael bacteria are the biofilm pioneers. There is no stronger organism identified including pseudomonas and staff and Demopoulos and aspergillus and legionella. No organism thrives as well in biofilm as michael bacteria. And that's one of the reasons why it's hard to get rid of it in vitro. You can't kill it and it's hard to get rid of it. And the patient as well. It's very hard to get into that biofilm to kill the organism. Um Allergic broncho pulmonary aspergillus is back to a patient interesting proposal. Um We're running out of time so I'll go through it quickly. But it turns out that why aspergillus uh get down to the fourth bullet point. So um uh they consider the term aspergillus allergic fungal airway disease. Allergic fungal airway disease because aspergillus is a thermo tolerant filament. This funding fungus that can grow in your lower in your lower airways so once it does that it stimulates allergic response. Um With I G. E. N. E. S. Cinephiles. So use of cortical steroids increasing use of anti t to biologics have been proposed um antifungal that's not antiviral and fogo bronchitis perhaps use anti antiviral antifungal. But but the thought about how this all happens is because aspergillus is unique and if you have a damaged airway already aspergillus will grow there and cause more damage. Alright aspergillus will grow there and cause more damage. So it's a self perpetuating problem. So back to our patient, he has bronchitis is he has MAC, he has broncho, pulmonary tuberculosis has swallowed function. Maybe had a history of sarcoidosis cause some damage. He had 9 11 exposure which works in ways that we don't know completely and bronco dollar responses. So why is this man coughing dancers yet all the above. So one of the lessons for patients like this is always keep looking. Don't know satisfaction of. So if you find the reason for coffee of bronchi exorcist, look for the MAC. Check for the fungus, see if it's relevant check to swallow because that may be why they have problems with bronchi exorcist and MAC to begin with, it's a very careful didactic evaluation you must do as an entry level evaluation of patients with bronchial emphasis. Now, if you have a patient with minimal bronchi exorcist who's not symptomatic, maybe you can surveil that patient somehow. We're not really sure that has not been worked out. But this is a very important thing, you gotta keep looking and look frequently. So the takeaway from all this. So despite increasing awareness of the prevalence of bronchi texas continues to increase around the world, there's ample evidence saying that bronchi excesses in the asymptomatic patients may be worthy of intervention. So there are no guidelines yet, but at least keep that in mind that patients you care for because the chest cT is the portal for diagnosis bronchi texas be precise and interpreting. Make sure that that the radiologist you work with are good at it and make sure that you're good at it too because you know if you find it, it's a comprehensive program. It's not a quick fix, It makes you busy and the patient busy. All bronchi emphasis has to be considered for now and later. So you want to take care of the patients exacerbation now you want to prevent their exacerbation later this winter and you want to prevent their excessive you want to prevent the bronchi access from getting worse and I can't emphasize that enough. And you have to emphasize that the patient as well when you do your airway clearance today so you won't have worse disease. Uh you know, 10 2030 40 50 years from now. You want to seek the underlying ideology. We talked about that just now and irrespective of coexisting conditions like COPD rheumatoid arthritis, chronic rhinosinusitis, Indecent affiliate manage the treatable traits if they have secretions, manage secretions, however they got there. However they got there and bronchi exorcists must be approached from the vicious vortex algorithm infection, airway clearance, inflammation and containing airway damage. So we covered a lot today. I thank you for your patience. Um I hope this shed a little bit of light on where it comes from, how to manage it and what to look for going forward. I thank you all Published January 3, 2023 Created by
