All right, we'll go ahead and get started. I want to welcome everyone to our panel discussion, Updates to the Asthma Diagnostic Toolbox. And we have a special focus today with the subtopics of oscillometry, bronchodilator reversibility, pheno, and bronchoscopy. And I have a bunch of fellow panel members here. We're going to talk about each of those subtopics. My name is Patrick Donahue, I hail from the University of Rochester in Rochester, New York. I also have Dr. Khan here from the University of Kentucky, Dr. Akuthoda from UCSD, and Dr. Moseson from Portland. And our plan is we're going to talk about each of these subtopics in succession, and we'll leave some Q&A and discussion for the end. So hopefully you all enjoy. So I'll get right into it then and talk about our first subtopic, oscillometry. My goals today are to give a little background about what oscillometry is, what it measures, and how the tech works. We'll go over a little bit about the evidence for its use in asthma. And at the end, I hope to give you some tips on how to incorporate this tech into your own clinic. So we'll start with a case, a 33-year-old female who presents to your asthma or pulmonary clinic with episodic dyspnea. She receives steroids and inhalers regularly for flares in her breathing. When she goes to do spirometry, she has some difficulty with it. And so this is her spirometry. And even for those of you in the back who can't read the numbers, you can probably see from the flow volume loop that the flow volumes are pretty atrocious, right? So this gets a test quality of F, which per the ATS interpretation guidelines is basically unusable. So my goal over the next several minutes is to kind of convince you that oscillometry is a viable alternative in this type of patient to give you some insight into lung mechanics and hopefully get to that asthma diagnosis that you're suspicious of. So oscillometry is a technique and involves a device that's kind of outlined right here. Typical oscillometry device has a loudspeaker on one end that generates some pressure waves, some sound waves that are superimposed over tidal breathing, reverberates through the lung and the bronchial tree. And then at the mouthpiece, there's pressure and flow that's measured. And through those measurements, again, we get some insight into lung mechanics. And the big takeaway and the contrasting feature to spirometry is that there are no forceful maneuvers. So much like the patient in our case who clearly had some difficulty with the spirometry maneuver, you would imagine that this patient would have a much easier time with oscillometry just because it involves tidal breathing, completely effort independent. So getting a little bit more into some of the details. This isn't an extensive talk on the mechanics of oscillometry, but just a little bit of insight into what's being measured. Pressure and flow are being measured. And from those pressure and flow measurements, we're able to derive respiratory system impedance. And just as a reminder, respiratory system impedance, that's the sum of all the forces air needs to overcome to go in and out of the lungs. Just kind of illustrate that right here. This is meant to represent normal tidal breath. So y-axis is flow, x-axis is time. Those little reverberations over the tidal breath are meant to represent the sound waves at different frequencies over the tidal breath. What that does is it creates a complex frequency function that thankfully we have some computers that can go through that data, perform a four years analysis, and give us something workable on the other side. So this is just by convention what an oscillometry plot looks like. The y-axis representing respiratory system impedance, and the x-axis representing the range of frequencies of the sound waves applied. And respiratory system impedance has two main components that we care about. The red representing resistance, so that's like a resistance plot on the oscillometry plot, and the blue being reactants. The way to kind of conceptualize this is the resistance, that makes it a little bit easier for all of us, that's like the airway narrowing and the airway caliber. So in asthma you expect the airway caliber to get narrow, the resistance to go up. Reactants, that's more reflective of the elastic property of the lung, lung tissue stiffness. But in the case of asthma, we think it kind of reflects ventilation heterogeneity, so airway closure and air trapping. So that can be abnormal in asthma as well. Again, this is the oscillometry plot, the y-axis representing impedance, x the range of frequencies, and there's lots of variables you can generate from an oscillometry measurement, but the ones that we are most interested in, the ones that seem to be implicated with clinical outcomes are the ones that measure small airways dysfunction. So the ones I would encourage you all to get familiar with are the R5, R20, this is also called the frequency dependence of resistance, and that's the difference between five hertz and 20 hertz, the resistance between those two frequencies. AX, which is the area under the reactants curve, and X5, which is reactants at five hertz. And these variables and oscillometry measurements in general have been implicated in asthma and other obstructive lung diseases. So going back several decades, because oscillometry is not a new technology, it's been around since the 1950s, it's been shown time and time again that it can be abnormal in different disease states. So for instance, in asthma, as airflow obstruction increases, resistance increases, and that's demonstrated on the top plot there. The lower plot is a more normal patient, and as airflow obstruction increases, resistance starts to increase. And the inverse is true for reactants, it becomes more negative as airflow obstruction increases. But a lot of our patients have normal spirometry, or have preserved spirometry with asthma. So it's actually been shown, and this is a great study that looked at comparing healthy patients to a cohort of asthmatics with preserved spirometry, looking at oscillometry measurements. And in particular, the AX, the area under the reactants curve, alone, or in combination with FEV1, was associated with an asthma diagnosis, and that's what this receiver-operator curve is trying to demonstrate. And I want to include this study, too, just to kind of really emphasize the sensitivity for oscillometry as a measure of small airway dysfunction. This is from the Atlantis study from the Lancet last year, and what this group did was they looked at several different measures of small airway dysfunction, so multiple nitrogen washout, tons of CT chest indices for small airway dysfunction, and oscillometry as well. And what they concluded was oscillometry, which they used this ordinal score as an outcome, which is a combination of the three main variables that reflect small airway dysfunction, R5, R20, AX, and X5. This ordinal score independently predicted or was associated with exacerbation risk. So this was a model which included other variables that are associated with asthma exacerbation risk, and oscillometry alone was predictive. So increased ordinal score, or just abnormal oscillometry variables for small airway dysfunction is associated with a lower ACT score and an increased risk of exacerbations. So incorporating oscillometry in your own clinic shouldn't be too challenging because it's a pretty easy to perform and administer technique. Shouldn't really interfere with your other common lung function measures, so it can be measured at the same day as spirometry. Per the ERS, per the technical standards for oscillometry, it's recommended that you do it before spirometry, and the rationale there is that the deep inspiration and forceful exhalation could potentially interfere with some of the variables measured. But also, and Dr. Khan is going to be talking about bronchodilator reversibility in a little more detail, so I won't spoil this too much, but bronchodilator challenge, you can incorporate oscillometry with that as well as a standalone test or at the same time as spirometry. And there's a growing body of data to suggest that using bronchodilator challenge with oscillometry enhances the diagnostic quality of the test. Interestingly, you can use oscillometry with a bronchoprovocation test as well. What's interesting about this is because it's done over tidal breathing, you have potentially less influence of laryngeal constriction with a forceful maneuver, so potentially less false positives. What's also been shown in validity studies comparing oscillometry and spirometry is that a lower overall methacholine dose is needed for a positive test. I'll leave you, and I'll emphasize this too, that I've been trying to emphasize the sensitivity of oscillometry. It's really important, like any test that we look at, to interpret in context. So a single abnormal variable can be seen in a percentage of a healthy population. So caution just interpreting single abnormal values. But also, while there are different patterns that can reflect different disease states, in general, oscillometry is not the best test to discriminate between different types of lung disease, which is kind of interesting. So to kind of summarize my portion of the talk, oscillometry is a great non-invasive effort-independent test, not a huge burden in your pulmonary function lab, pretty easy to administer. It's basically the go-to test in pediatrics, but it can be useful in the adult population too. So in the elderly, patients who are weak, patients like the patient in my case who had poor coordination. And there's a large body of data showing that it's very sensitive for detecting abnormal airway pathology. So it potentially has a good use in patients with preserved spirometry who have asthma. And there's good data to suggest that it predicts future loss of asthma control. But more study is, of course, needed to kind of really, I think, solidify this as a routine test. So that's all I had for you today on oscillometry. And I look forward to our next talk. I think Dr. Khan is up next. Bronchodilator Registration. Thank you for the introduction. So again, my role today is more talking about bronchodilator reversibility or responsiveness really, right? And you already know me. Again, the objectives here were, again, when I was looking through it, and as I'm sure we've all seen, number one, trying to understand is reversibility and responsiveness the same thing, right? And trying to see if there is a difference between that and how it impacts how we take care of our patients. During this, we'll also review the 2005 ATS recommendations of how we interpret the bronchodilator response, its limitations, and essentially those limitations sort of what led to the updated guidelines for the 2022 bronchodilator response. And then ultimately briefly discuss about the role of bronchodilator response in the diagnosis of asthma, right? How important is it? Or is it as important as we think it is, right? So first, I'll do a little old school way of doing it with raise of hands. Do you guys want to say, do you think there's a difference between these people who think these are the same terms? They can be interchangeably used? Okay. So a few hands, right? So good learning point, right? So again, reversibility really is the normalization, right, of the ratio, right? So what it essentially means that the obstruction which was present on a pre-bronchodilator test, once you give them the bronchodilator test, it normalizes, right? It's just a qualitative term. And then if you think about it, right, but purely by definition, it sort of rules out your post-bronchodilator obstruction or the fixed obstruction, right? I know this is an asthma talk, but from a goal standpoint, which defines COPD as a post-bronchodilator obstruction, by definition, if somebody has the reversibility, they will not qualify for the diagnosis, right? On the other hand, the bronchodilator response is actually a quantitative term, right? Which means there's a specific change in either FEV1 or FEC, and it's linked to some evidence-based minimally clinically important differences, right? So it does not need to have normalization of the ratio, essentially. And then the updated guidelines sort of address this issue, and they specifically use the term bronchial responsiveness and reversibility when they talk about this. Just going into the 2005, I think this is something we've been, I guess, playing or using since 2005, and then we know that they defined it as an absolute and relative change from the baseline greater than 12% or 200, both have to be present. And we'll see there's a lot of limitations which this brings along with it, just being an absolute change in itself. So the first one is essentially that this is the bronchodilator response, if calculated from absolute values, sort of is dependent on baseline lung function, right? So what it means is that somebody who has severe lung disease, they may be able to generate a 12% change, but they may not be able to get a 200cc change with it, right? And on the other spectrum, somebody who has no obstruction, as we heard, most asthmatics may not even have a normal or preserved spirometry, they may achieve a 200cc change, but may not have the 12% change which was mandated, right? And then this was looked even further that the relative change, and this is the same thing, the relative change in FEV1, as you see, as you move towards the very severe spectrum, the relative response in FEV1 was pretty drastic, the red curve, right? And when they compared it with the blue dotted line, which is the FEV1 greater than 8% of the predicted value, it sort of leveled the playing field, right? So that took away that limitation that people with severe disease may not necessarily have a severe bronchodilator response to it, right? And the second limitation which obviously comes with anything when you time absolute values is that they are dependent on the height, age, and the sex, as any spirometry is, because they're not using the predicted values of absolute value, right? So a smaller person and a bigger person, height-wise, will may have different, they will have different lung functions, and the absolute value of 200 may not fit on everybody, right? So the whole idea was that by using a percentage change from predicted values for a given age, sex height sort of mitigates that limitation which comes with it. So the rationale to consider changing it to the percentage predicted sort of, this can be summed up as, number one, trying to minimize the limitations we talked about, maybe trying to incorporate a survival signal, if you have, using predicted value, and then data from the epidemiological data, like what is the right change, right? We talked about that, and then talked about the limitations already. From a survival advantage point, it was looked and published in CHESS in 2015, where they looked at about 4,000 people, and they compared people, the survival, essentially, by using two metrics here. So the dotted Kaplan-Meier curve here shows the people who had FEV1 greater than 8% of the predicted, and the solid line is the standard 2005 guidelines. And they had a survival advantage, and the reason they came up to the 8% predicted, that was the optimal survival advantage they calculated doing their analysis, as compared to those who did not have it. This is one study, so take it with a grain of salt, but yes, there was a signal that it may be, if you use this by the bronchodilator response of predicted, 8% of the predicted value, it may have a survival advantage, which can make the utility of this test more, because then it adds a prognostic value to doing this test, right? The 10% change in the predicted value comes from a lot of epidemiological studies. This is one of them. As you can see, they had multiple centers all throughout the world, really. And then the 10% comes from, that's the upper limit of the range of bronchodilator response in healthy individuals. And then in their analysis, they looked at all the different values, FEV1 based on predicted, and they found that the change from the predicted value had the least cross-site heterogeneity, was independent of sex, and stable across all goal stages. So they recommended using 10% FEV1 change predicted as the value to be used for assessing bronchodilator response. So all of this sort of led to the updated guidelines, which I'm sure most of you have already seen. And they are, that now is classified as a change greater than 10% relative to the predicted value of either FEV1 or FEC, right? So they've taken away the baseline and moved that. And this is the basic formula that's available. It's pretty much similar to the last one. The change obviously is denominator. Now it's a predicted value rather than the baseline value there, which was present there. And the predicted values are generated by the GLI spirometric equations. So hopefully by now we have an idea of why we think there was a need to update these guidelines, and then the rationales and the limitations of this one. But obviously nothing is perfect, right? So they've looked at the impact of these new guidelines on asthma. And this was done, published recently when they used the same old and the new guidelines on about 4,000 asthma patients. And they found that by using the new guidelines, the number of people who had the possibility of having a bronchial response reduced by about 10% as compared using the 2005 response. And then looking at the, remember the severity we talked about, right? So the impact of severity on the bronchial response was consistent with what was seen in the other trials where it followed the same inverted U pattern, but the effect is minimized, right? So again, this is a good thing that we think that that takes away the effect of severity on bronchodilator response itself. And then the last part I'll just briefly talk about and leave some food for thoughts of where we go and how we use bronchodilator response really in our everyday management of asthma. Again, an ideal test is a test which has either a good diagnostic benefit or it has some prognostic value to it, right? Either that's treatment versus mortality as a benefit. And we'll take a few minutes to see whether bronchodilator response testing, which we do very frequently, adds to that or not, right? So again, is there a diagnostic benefit for asthma, right? So biggest rival to asthma really in obstructive lung disease, which we see is COPD, right? So the biggest thing we have to figure out, is this test good enough to differentiate between obstructive lung diseases, right? As we discussed, oscillometry may also have the same downfall where it may not pick one or the other. But again, for COPD, they've looked at that. This is, again, a multi-analysis of three large population-based studies, and they found that people with asthma and COPD had about 17.3 and 18.4% bronchodilator reversibility. This is, again, based on the COPD gene study, Barton and all showed that the prevalence of bronchodilator reversibility in COPD population was 32% or 44%, based on, depending on which recommendations you use. So essentially, it boils down that bronchodilator response is at least as common in patients with smoking-related COPD as those with current asthma, right? So it sort of defeats the notion we've been, I personally had that, hey, I mean, if there's a bronchodilator response, it has to be asthma, right? And that's actually not the case when you look at it, right? So in the right settings, it can support the diagnosis, for sure. But in isolation, it's not a very sensitive or a specific test to just diagnose asthma with it. Again, prognostic value, we talked about one study showed that there is a possible survival advantage if you use the bronchodilator response greater than 8% of the predicted value. But others have shown that it is really not a survival benefit, no matter how you use it. Again, the same study which Barton and all did showed that no matter which bronchodilator equation you used, if you adjusted for severity of lung disease, there really wasn't a signal towards exacerbations or predicting exacerbations or mortality, right? So again, it leaves us with questions that, yes, this is a test we use very frequently. This is a test which somebody who is able to do good spiral, right, first step, right? If you can do that, then yes, bronchodilator, we do it. But if it's a positive bronchodilator response, we just have to be careful how we interpret it, right? Number one, using the new guide. And also, even if it's positive by the new guidelines, is it enough to label somebody with asthma or not, right? And that is why we are having a session where we can incorporate all the tools we have and figure out are we even making the right diagnosis, let alone then doing the right treatment. So to summarize really, bronchodilator response is defined as a change in 10% relative to the predicted value now. This addresses the limitations of the previous guidelines, minimizing the effect of age, height, sex, may have a survival advantage, and it's backed by large epidemiological data. It also may mean that in real life, there may be a decrease in the number of patients or asthmatics. We previously had bronchodilator response, may not have bronchodilator response using the new guidelines. And then obviously, it's not specific to asthma, right, and may have a limited role in asthma, right? So I hope I've left you with some thought-provoking things, and I'm happy to take questions at the end of it. And thank you. Thanks, Patrick, and thanks for the invite for the session. Thanks for the organizers as well for having me. As you all probably gathered, we're going to be doing some Q&A as a group at the end, so it can be a mix and match of the various topics and maybe some crosstalk between the topics as well. So I will be talking in my part here about pheno-testing. That's me looking a little less casual than I am in our Hawaii Convention Center today. These are my disclosures, hopefully none of them relevant to this presentation. So just to go back and think about why we measure pheno in asthma, this goes back to the early 90s. There was a lot of science that was happening very quickly with respect to nitric oxide as a molecule. In 1992, nitric oxide was the molecule of the year in science, because all of a sudden we're learning of the very potent effects of nitric oxide in multiple systems, in particular cardiology with coronary vasculature, et cetera, and asthma was no exception. This paper from just after that science molecule of the year issue showed that exhaled nitric oxide is increased in asthma. This is a very different methodology from what we use today in our point-of-care nitric oxide testing, but in this figure, this is over time collection of nitric oxide into a vessel. So you can see in the top graph, which is people with asthma, versus the bottom graphs, which are normals, that nitric oxide is very much elevated and collects in a greater amount over time compared to normals. So this was one of the very first demonstrations that nitric oxide could be used as a biomarker, might be an indicator of dysregulated mechanisms in the airway in asthma. You know, in 12 minutes, I can't go over a lot about mechanism, but the potential effects of nitric oxide in the airway in asthma are profound, and I'll point to a couple of things here. Nitric oxide is produced through a couple of enzymes that are nitric oxide synthetases or synthases, a constitutive NOS and an inducible NOS. And the nitric oxide that's produced kind of normally in the airways dilates smooth muscle, which is a good thing in airways disease, presumably. But what we see from inducible nitric oxide is the potential for NO to be acting in potentially dysregulated ways, promoting inflammatory mechanisms, cytotoxic mechanisms. But for our purposes in the clinic, we rely a lot on nitric oxide really as a biomarker, kind of a combination of all of the nitric oxide that's produced. And a lot of what we see, presumably, is driven by epithelial cell production of nitric oxide under the control of IL-13 acting on epithelial cells through the IL-4 receptor alpha. And then that's excreted into the luminal side of the airway where we measure it. And Patrick, I promise I won't laser you with this while I... So, and based on that, we use nitric oxide in various ways. And there's the obvious that we're all doing in the clinic these days in trying to figure out what biologic we might give to somebody. I'll get to that toward the end. But there are other ways that we can use exhaled nitric oxide. Now with our more modern point of care devices, which test nitric oxide in concentration rather than in collection over time. So, exhaled nitric oxide can be a marker of inhaled corticosteroid adherence. In this paper, now from 10 years ago, if you take patients with asthma who are predicted to be, through various surveys, are known to be either adherent or non-adherent. And they have similar nitric oxide levels. So you start at 100% of your baseline nitric oxide. Then you observe them taking inhaled corticosteroid. In the patients who are known to be non-adherent, they have a much greater drop from baseline in their exhaled NO compared to adherent patients. So that's one tool that we can, or one way we can use exhaled nitric oxide as a tool in the clinic for understanding whether our patients are adherent to their inhaled corticosteroids or perhaps not taking their inhaled corticosteroids correctly. This is not necessarily something we think about from an individual patient perspective, but kind of in the aggregate, exhaled nitric oxide is a predictor of accelerated lung function decline. This paper from the Netherlands, from Elizabeth Bell's group, I'll actually just point you up toward the upper right. Sorry, it's way too small. It's probably small for you too. This, the upper left. So this is exhaled nitric oxide over five years. Or this is exhaled nitric oxide predicting lung function decline over five years in a cohort of 200 patients from the Netherlands. And the higher the nitric oxide level, the more you see a reduction in FEV1. And in a multivariate analysis, an exhaled nitric oxide level of greater than 57 parts per billion actually was statistically significant in predicting lung function decline. So, you know, FENO there tells us if FENO's elevated, this person might be more likely to lose lung function. And yes, we do use FENO for diagnosis and for monitoring as well. This is the 2011 ATS Clinical Practice Guideline, which many of you are familiar with, where we think about exhaled nitric oxide in kind of a negative group, a positive group, and an in-between group where things aren't so clear. But from a diagnosis perspective, a FENO of greater than 50 is somebody who may have type two inflammation. It kind of supports an asthma diagnosis. These are patients who are likely to benefit from inhaled corticosteroids. Conversely, the low FENO groups, you might want to think about an alternate diagnosis. It could be asthma, but you start to think a little bit more, is this really asthma in those patients? And these are patients who may be less likely to benefit from ICS. Obviously, these are not absolute, but these give us some, start to give us some guidelines or some ways to navigate using exhaled nitric oxide for diagnosis. And then the patients in the middle with FENOs of 25 to 50, this is a little tougher, but as you get particularly above 30, above 35, you're feeling a little bit more confident about both your diagnosis and about the presence of type two inflammation in the airways. And yes, FENO can be used for monitoring as well, again, might let us know about adherence, might let us know whether the ICS dose is inadequate and might need to be stepped up, might let us know about whether technique isn't quite right, whether we might have to make some additional efforts to educate our patients about technique. So there's, again, nothing's a perfect science. We're learning that with oscillometry. We're learning that with bronchodilator testing. But in concert, along with, together with clinical context, we can start to deploy FENO along with these other tools for making diagnosis and monitoring as well. So the most recent statement about FENO was led by Shamita Khatri here, who was actually originally slated to give this talk, but kind of happily and sadly, she took a job at the NIH and she can't, she couldn't give this talk, so I stepped in. I had the pleasure of participating under her lead in this statement about using FENO to guide treatment decisions in asthma. And then we went through the evidence. There's a lot of decent evidence, that's definitive about exactly how to use FENO for guiding treatment decisions, but we took all of that evidence and one of the things we came up with was this matrix of using exacerbation rates and FENO in kind of a two by two matrix to think about what to do next with patients like this. So somebody who's exacerbation prone or has poor asthma control and has a high FENO, this is somebody that you should step up therapy. This is a type two patient who you might consider biologics in depending on their severity. And then conversely, if they're exacerbation prone with the low FENO, really to address confounders, think about alternative diagnoses, et cetera. So a lot of common themes in these statements and this evidence, but I think if you, this particular statement really focuses on that question of can we use FENO to guide treatment, which increasingly we can. So I wanna move next to this concept, again, related about using FENO and parenthetically blood eos to reduce preventable risk. Ian Pavard from Oxford has championed this now for several years. You'll notice the date on this is 2013. So he was writing about this a decade ago, but you're seeing this idea of FENO as a treatable trait being more and more promoted. And this concept is very similar where if you have a lot of symptoms, you have preventable measurements of preventable risk like FENO. This is somebody who has severe concordant disease and you might consider stepping up therapy in those patients or potentially using biologics. And again, writing about biologics even before we had a lot of biologics available. And Ian, along with Simon Couillard from Cambridge Canada published this paper last year, which really gives some evidence, some quantitative evidence for using FENO as a treatable trait in asthma. So then they call it the Oracle Index. So what Simon and Ian did is they took the placebo group from a bunch of clinical trials in asthma and looked at the exacerbation rates in these placebo patients. And found, I won't go through this in detail, but that blood EOs and FENO could predict, regardless of genus step or other clinical risk factors, what their exacerbation rate might be. So these red boxes are higher exacerbation rates and FENO correlates, elevated FENO correlates with having an increased exacerbation rate. So it's really a treatable trait that's predictive of poor outcome. And yes, we are all now using FENO as a biomarker for thinking about what biologics to use in clinic, as in our clinics as well. There are the biologics where FENO is not predictive, like our IL-5 therapies. This paper shows that FENO is not predictive of mepolizumab response. So you can see down here that, well, you can see in the lower part of the graph that the low FENO group and the high FENO group had very similar outcomes. So FENO was not discriminatory, as opposed to dupilumab, where FENO is quite discriminatory in predicting response. And even with tezapilimab as well. Again, I don't know if the laser's working very well, so I won't try, but toward the bottom of the graph, you'll see the higher FENO groups have a better improvement in exacerbations than the lower FENO groups. So the drug works well in both low and high groups. So I'll stop there. Hopefully I didn't go on too long and left room for our Q&A session. So thanks. Thank you very much for having me. I have no disclosures. These are our lesson objectives. We're going to go over the available literature on the utility of bronchoscopy and asthma, talk a little bit about risk. I'm going to go over a couple of cases, and I hope to leave you with some thoughts about when to proceed with bronchoscopy and asthma. Just to be clear, in case anyone wants to leave now, this is not a bronchial thermoplasty talk. I got this email in April, and I have to say I thought it was addressed to the wrong person because it was asking me to talk about the utility of bronchoscopy and diagnosing asthma, and my response was, what? But they did mean me, so I'm going to try to help navigate this. Whenever I'm really trying to think through something and the adult literature is leaving me cold, I actually start looking into the wisdom that we can find in pediatrics. I have three young children, and I think, like anyone who's gotten to know their pediatrician, they recognize that there is just so much wisdom there that we could all use in the adult world. So I thought this was a helpful paper, which I always kind of think about when I start talking to people about the role of bronchoscopy and things for which we have limited data. Most people are very strongly of one opinion or the other, and so I thought this was a helpful way to go through it. It covers the history of bronchoscopy a bit, which prior to the introduction of inhaled bronchodilator therapy, bronchoscopy had a very interesting history in asthma, including being used as a method of medication delivery, where you could, you know, people would be instilling things like epinephrine and tonics into the lungs for our severe asthmatics. Fortunately, we don't do that anymore, and bronchoscopy generally in the adult world has become much more of a research tool. But this is kind of a comprehensive look at when bronchoscopy can be useful in pediatric asthma, and one of the things they noted is that, you know, in bronchoscopic evaluations of children kind of characterized as either having severe asthma or not, you can actually see different antigen and infectious markers in the BAL fluid that kind of, that may be targets for treatment to try to get, you know, inflammatory disease under control. Unfortunately, I think all of us are frustrated by the fact that what's going on in the lungs is not often easily reproduced by what's going on in the bloodstream, right? So you can find serum eosinophilia in the blood, but sometimes that doesn't really tell us what's going on in the bronchioalveolar lavage fluid or, unfortunately, on tissue biopsy. And the other thing is sometimes you just get surprised when you actually go in there with a camera. So this is a syndrome that's been described called airway autoimmune inflammatory response syndrome in peds, where, you know, finding this kind of nubbled mucosa that ends up being biopsied. And there's a similar, not quite the same, but similar disorder in adults called asthmatic granulomatosis, right? So this is actually something that is much more of an autoimmune disease that actually requires immunomodulating therapy. So this was a series that went through patients who were found to have this lesion. And they, if you look on the left, I'm going to try the mouse because it's a bright green arrow and I was hoping that would be helpful, but it is not. So we're back to the blinding laser. So if you look on the left, you see the prednisone dose, because these were patients who were referred for basically refractive seeming asthma and ended up having asthmatic granulomatosis. And you can see the prednisone dose that they were on before they ended up getting started on azathioprine for the most part, right? And then you actually had an improvement and able to kind of drop the treatment of what was actually truly an autoimmune disease far in excess of what we think of as asthma, which obviously has immune components to it and able to get, you know, some improvement in disease control. So where did this group of very smart pediatricians land is they actually came up with looking at considering bronchoscopy, you know, when you're getting up into these higher steps in asthma. So looking at it, whether either when you're really kind of moving along, you're dealing with someone who's on high dose inhaled steroids and considering, you know, before we start biologic therapy or if they've started biologic therapy and they're not responding, is this something we should consider? And then what did they do? So you can do a lot of things once you're down in the lungs, right? You can do all sorts of things. So they did VAL, they did the airway examination, cell count differential, and they didn't just do cultures. They actually did PCR looking for infectious pathogens and if anything was abnormal visually, they biopsied it. So then of course, trying to do a review of the medical literature for adults is very frustrating because there's not much. There's this one paper of 58 patients at National Jewish where they, you know, excluded vocal cord dysfunction and they were basically going and evaluating these patients who had been referred to this referral center for really difficult to control asthma and also did, you know, testing as much as they could for acid reflux with esophageal testing. They had this very protocolized bronchoscopy approach where they actually evaluated something called the superglottic index, which basically looked at markers of inflammation in the glottis. They did a bronchitis index and they did a VAL endobronchial biopsy and brushing on everybody with asthma. So these people had stones. So what did they find, right? So they really worked on kind of trying to phenotype the types of asthma and kind of break them down into five groups. So they're either kind of a GERD predominant group, a like a subacute bacterial infection group, a tissue eosinophilia group, a mix, like often a mix of more than one of those things, or just nothing, that this didn't really help them sort the patients at all. And what did they find? So actually around, you know, two thirds of the patients actually had a really high superglottic index. They had a lot of inflammation, mucus, you know, redness in the upper airway. And of those patients that had acid reflux testing with it, a lot of them, you know, most of them actually had documented GERD. And then the patients who didn't have a lot of that inflammation around the vocal cords going into the airway, of those who had acid reflux testing, very few ended up showing signs of acid reflux. And then 25 of the patients, around half, had a subacute bacterial infection, if you're defining it with a positive culture or a positive PCR. And the polys on the BAL were actually kind of helpful in suggesting that, but not 100%. And then again, like with the kids, it doesn't, like whatever, your serum eos are kind of helpful probably, but they're not going to give you the slam dunk answer about what's actually going on in the lungs. And so, but the one thing that was interesting, so these were the different infectious phenotypes that they pulled out with either PCR or culture. And what they decided to do with these patients is treat them for their pathogen. But just look at the treatment courses over here. We're talking 14 days, 30 days, six months, right? Very long treatment courses with antibiotics. And that starts to, of course, raise in my mind the amazes trial of azithromycin, you know, when you start kind of looking at that was there, what they did with it. And so did this matter, right? So they brought all these people. Did it help? Right? So if you had one of the typable phenotypes, like the GERD, bacterial infection, tissue eos combo or nonspecific, or those four, not the nonspecific, and they kind of decided whatever they wanted to do in their clinical evaluation to target therapy. So whether they gave you, you know, six months of azithromycin, whether they just really doubled down on your acid reflux, whether they used the one biologic available at the time, which was omelizumab, whichever direction they went, it really did seem like they had improved your ACT score later, unless you were in the nonspecific phenotype, which was the one where we did a bronc and it didn't help us, it didn't point us in any direction, right? And then kind of similarly here, there was maybe some changes in FEV1, except again for the nonspecific phenotype. Now, of course, you can drive a Mack truck through all the caveats and questions and concerns about this study and whether it should be used. Mostly like these are really prolonged antibiotic durations, like I'm, you know, not usually prescribing six months of antibiotics for a patient. Was this just regression to the mean? Was this just like they bronc them at a bad time and then, you know, eventually most people get better? Was this a placebo effect? I would say one of the things that maybe goes against that is that the nonspecific group didn't seem to get any benefit out of this procedure. This was also prior to other biologics. This wasn't including anything about, you know, pheno. The other thing that's really, that I really care about in terms of the spirit of first do no harm is it really didn't talk about how well did these 58 patients tolerate the bronchoscopies, right? Which is I think what we all want to know. So what is the risk of bronchoscopy and asthma? Again, and please, if any of you have some other studies out there that you can just tell me about, hit me after the talk because I went down a deep dive looking for these things. So, you know, there's all these kind of like anecdotes, like in the 1970s, they're like, ah, I bronc this person, they did bad. And then another one, you know, talking about this is my technique. I gave everyone, I gave this person I was broncing 100 milligrams of methylprednisolone and some nebs right before and they did okay. So maybe we should do this. This is a caliber of research. So I found four studies that I thought might kind of help slightly answer the question of risk of bronchoscopy and asthma. And I kind of tried to make a table of them, which is, you know, this is certainly not, you know, comprehensive, but it's my best estimate. So this was a study that actually had the most asthmatics. It was 159 asthmatics, which is apparently a giant study for bronchoscopy and asthma, over 273 bronchoscopies. All these patients were premedicated and around 12% of them had adverse effects. In two cases, the procedure was terminated, three of them were admitted to a hospital. And then other, you know, there was other, you know, some people needed nebs, you know, some other complications ensued, but nothing devastating. Then to another study was part of a COPD study. So this was only 16 patients who self-identified as having asthma and 239 patients who had either COPD or no disease. And they also got premedicated with SABA and ipratropium, and 6% of these had early termination. One of them had severe bronchospasm needing IV treatment. One of them actually got CPR, but they got them back. And of note, this excluded people who had ongoing respiratory symptoms. So like if you're thinking about bronching someone who has asthma and active symptoms, it's a thing to think about. Then two other studies looked at were kind of more research cohorts, and they were actually looking at, so you could dive down into the patients who identified as asthma and what happened to them, and they actually kind of came to slightly opposite conclusions. So they had kind of a primary composite endpoint of, you know, respiratory trouble, needing a nebulizer, et cetera, you know, complication of the bronchoscopy. And in the first study, which was, you know, 233 patients, which was a pretty sick cohort, like a third of them had cardiovascular disease, 40% of them had chronic lung disease. And then having asthma was actually protective against that primary outcome. And I could imagine, if I made it up, that maybe the asthmatics in that study were younger or something. In the other study, they actually found that this was a COPD research cohort, they actually found that people self-identifying with asthma had a kind of increased risk of that primary composite outcome. So what do we do with this? You know, if you think about this, there was five hospital admissions and around 289 bronchs of people with asthma. Maybe it's around 1% to 2% of people who are going to get a bronch with asthma end up in the hospital. So I'm just going to quote something to your patients with very limited data. So I'm just going to talk about a couple of cases that I've come across that have made me think about this a little bit. So this is a lady admitted to the hospital on bad asthma exacerbation, needing oxygen, which always makes us nervous when someone's got asthma and needs oxygen, wheezing, ongoing distress, got five days of azithromycin, high-dose steroids, COVID negative, everything negative, D-dimer normal. She just felt like she was coughing up gummy worms. And so she ended up getting a CT before we had her pulmonary consult, and this is kind of what we saw. And we're like, all right, you're mucous plugging, you got Adalexis, VQ Mitchmash, et cetera, et cetera, et cetera. We're going to gingerly try a little hypertonic saline after we made sure the saline's okay, see if we can help loosen up those mucous plugs, do a bunch of IPV. She did that, felt great, thought we were amazing doctors, but she still stuck on two to three liters and still feeling really ill. And she's like, I can't take this. So we bronched her. And this is what we sucked out. And it was gross. And then she weaned, my partner who did this made sure to send off all these lovely studies, kind of neutrophilic, right? So thinking about our previous thing, the cultures were pretty much negative. Several weeks later, max growing, but now her CT has no nodules or anything, and she's feeling better, and she's going to follow us up in clinic. So it's made me think. I don't know how that one's ending, because we're still seeing her soon. Second case was a lady who'd had asthma as a child and then began to have worsening asthma. She got escalated up all the things, high dose ICS LABA, getting LAMA, all sorts of things, and just frequent exacerbations. And when she'd have an exacerbation, she'd have these little nodules at times that would always clear. She has all the bad things you do. She sleeps with cats in her bedroom, she won't get tested for sleep apnea, all the things. But she would have these intermittent nodules at times. So we bronched her. And she had terrible tracheobronchomalacia, very inflamed. But we did, her BAL did grow MAC, and I referred her for treatment. And she is now on Dallera PRN, and I see her once a year. And I had been seeing her monthly. And I don't know what to do with this. This is just a case that has made me think. She's still refusing sleep study, still has cats in her bedroom and won't, and shows them, and won't consider BiPAP or anything, because this is how she is. So when to consider bronchoscopy and asthma. So I would say when you might be wrong about it being asthma. So it would be my take home. Or when it could be asthma plus something else. So this is kind of where I have started thinking about this, where kind of like maybe exhaled nitric oxygen. Like I just, am I not quite sure that I've got this diagnosis correct, right? Because patients don't always read textbooks. Thinking about our pediatric colleagues, you know, when it's refractory asthma, despite high dose therapy, maybe, you know, when we're thinking about starting a biologic, or people just aren't responding the way we should, or if there might be, if you're really kind of thinking of a mechanical component, right, tracheobronchomalaceous, if your mucus plugging, or just kind of indeterminate cases. And then I would say there's not much data to guide us, but I would probably premedicate this person with a bronchodilator, if you're going to do it. So just some references, image sources. So thank you. Feel free to email with questions, or, yeah.

Updates to the Asthma Diagnostic Toolbox

oscillometry

bronchodilator reversibility

pheno-testing

bronchoscopy

spirometry

lung mechanics

exhaled nitric oxide

type 2 inflammation