Good morning, everyone. Thanks for being here at Current Controversies in Pulmonary Function Test Interpretation. My name is Tom Decato. I'm from Harbor-UCLA Medical Center, and I'm going to be moderating or at least attempt to moderate things today. And at a minimum, I will introduce our esteemed speakers who are all really experts in pulmonary function test interpretation and beyond. And so this is the order we're going to go in today. And so first up will be Dharani Narendra from Baylor talking about bronchodilator responsiveness. Good morning, everyone. I'm Dharani Narendra. Aloha and welcome. And we are getting it started about the controversies in pulmonary function testing. And my topic today is, what is clinically significant bronchodilator response? I work at Baylor College of Medicine. I'm the program director for the Critical Care Medicine Fellowship Program. No disclosures for this talk. And we are going to use some ARS. So the first question is actually ARS. So please use your phones to answer these questions. The objectives for today is to review the rationale for the new bronchodilator response, the definition that changed last year by the ARS and ATS. And we're going to assess the utility of the bronchodilator response in differential diagnosing in obstructive lung disease and also analyze the association with the clinical outcomes. So here we go. This is our first question. The optimal way to assess change in FE1 or FEC after administration of a bronchodilator is which of the following? An absolute shift from the initial value or a relative change compared to the initial value or a change in relation to the individual's predicted value, a combination of these. Is it activated? I hope. Okay. Let me go back. Sorry. Okay. In the interest of time, let's see. Okay. There's no clear answer, right answer here. It could be any of these, but I think combination of these is what I think is the most appropriate answer. So what is a bronchodilator response? It's a test to assess the change in respiratory function in response to administration of a bronchodilator. What does it do? It reflects the integrated physiological response of the airway epithelium, nerves, mediators, and smooth muscles, along with the structural and geometrical factors that affect airflow in the conducting airway. So that's what we're trying to assess. If you remember from the 2005, the ATS-ERS definition, it said that it's a significant response is considered anything more than 12% and 200 ml, either in FEV1 or FVC. And that's what we've been using for many decades, but the major limitation of this definition was that if you look at the absolute and relative change to FEV1-FVC, it was inversely proportional to the baseline lung function. You can see that study from E4U, any definition of bronchodilator response, either ATS-ERS or ECSC or change in FEV1 more than 8%, you can see the more severe they are, the more the bronchodilator response is. So it's inversely proportional to the lung function. And it's also associated with the height, age, and sex, which the 2005 didn't include. So the new 2022 ATS-ERS guidelines reported that change in FEV1-FVC as an increase relative to predictive value, which minimizes the sex and height bias. The bronchodilator response has been defined as more than 10% of the relative to predictive value of FEV1 or FVC. And what they also mentioned was bronchodilator response in relation to FVC rather than FEV1 was more reflective of physiological process of air trapping. So that was something important that came out from the study or guidelines. The way that we assess bronchodilator response is post-bronchodilator minus the pre-bronchodilator divided by the predictive value, which is to your appropriate GLI initiative spirometry equation times 100. Anything more than 10% was considered to be significant. Let's look at a patient here. This is from our patient in the clinic. This is a 53-year-old patient with dyspnea, 20-pack-a-year history of smoking. I had a PFTs done for assessing the shortness of breath. And you can see he had a PFT done in May and PFT done in September. And you can see here, he didn't have any bronchodilator response. There was obstruction. I don't think the pointer is showing, but you can see there's obstruction, but not much bronchodilator response. However, at the same patient, when done in September, you can see there was obstruction and good bronchodilator response. I don't know if I can point that, but... And the key here is that first test was not meeting ATS criteria. So it's important to know the basics that, you know, it has to meet our ATS standards criteria for us to interpret this. And for the test to be good, it has to have a good interaction from the patient, the technician who's doing it, and you need to have the appropriate machine too. So make sure all these three are effective so that we can interpret our PFTs. Coming to the next, the ARS question, regarding bronchodilator response, which of the following statements is accurate? So which is not true. It distinguished between patients with asthma and COPD. It's exclusively observed in patients with asthma. It predicts patients who will clinically respond to long-term bronchodilators. It identifies reversible airway obstruction, none of the above. Okay, in the interest of time. The actual answer is actually none of the above. So we'll see why. So does bronchodile response distinguish asthma and COPD? The answer is no. You know, there was a study done in 2019 that showed the prevalence of bronchodile response is 17% and 18% in asthma and COPD patients respectively. So that's why, you know, it's not unique just for asthma patients. This is a patient from my clinic, from our hospital, which shows patients with asthma having significant bronchodile response on the left-hand side. On the right-hand side, a different asthma patient not having a bronchodile response. That doesn't mean they don't have asthma. So it's not unique for asthma. Similarly, in COPD patients, you can see that the patients can have bronchodile response in COPD patients. And we will talk more about how almost 30% to 50% with COPD patients will have bronchodile response. That's what is shown in this slide here. Does it predict clinical response to long-term bronchodilitis? Several studies have done saying no, it doesn't predict a clinical response. So Dr. Hanania, who's my mentor, who's here, did a study in 2011 that showed it does not predict a long-term response to the theatropium, that's pariva. So the assessment of acute bronchodilitis response should not be used for clinical decision making when prescribing bronchodilitis to our patients. And there are other studies also that showed that bronchodilitis does not accurately predict the response for inhaled corticosteroids in obstructive airway disease. And there's a recent COPD River Breeze study that showed the short-acting beta agonist does not respond long-term treatment to indactorol. So do not use bronchodilitis response as the clinical decision for prescribing patients bronchodilitis. Does it predict phenotypes in patients with asthma and COPD? Probably. It does predict, like higher the FEV1 change predicts likely seen in asthma or asthma-like phenotype in COPD. And then, you know, bronchodilitis response has been used in one of the definitions for asthma-COPD overlap, both major and minor. You can see major if they have more than 400 mL change in FEV1 or FEV1 change more than 200 mL and 12% from the baseline, that's your old definition. So it does help you in identifying ACO, that's the asthma-COPD overlap. The next question is, does it predict outcomes in asthma-COPD here where it gets muddy? There are lots of studies that showed the greater bronchodilitis response is shown to have worse asthma control, both in adults and pediatrics. The second study here is showing that in 230 children, the children who had bronchodilitis response had low lung function for asthma control. However, there's a recent study from Dr. David Kaminski that showed, you know, he assessed the different bronchodilitis response using all these definitions here. The old ATS-ERS, the second one was the new ATS-ERS. They also used FEV1 more than 8%, increase in FEV1 more than 0.78 Z-score. And then these are like participants, actually poorly controlled patients from the participants of ALA, that's Airway Lung Association, where they studied patients with poorly controlled asthma, 931 patients. Of that, only 45% had bronchodilitis response, and 56% of these 415 had met all four definitions. You can see on the Venn diagram on the right-hand side that 56% having all definitions. So what did they find in this study? They found that bronchodilitis response was not associated with asthma control, asthma symptom burden. It had shown that like, you know, if you have bronchodilitis response, you may have low function or low symptoms, but it didn't translate in terms of statistical significance. So welcome to the confusion state again. And then in COPD, what happens in COPD? This was a subset of patients from COPD gene cohort study. Here again, Dr. Hansen and colleagues in 2019 checked determined patients based on FEV1 or FEC change. They were categorized into minimal, mild, moderate, marked. Both moderate and marked had at least more than 100 mL of change and minimal change in FEV1. If you use this definition, 80% met the criteria as shown on the right-hand side, whereas only 20% met the ATS-ERS criteria based on the old definition. So what did this study show? It showed that if you use FEV1, you know, compared to negative bronchodilator FEV1, the minimal, mild, moderate, and marked change categories had greater six-minute walk distance, lower St. John's respiratory questionnaire, and modified medical research council dyspnea score. And then also compared to the negative bronchodilator response, you can see on the right-hand side that the exacerbations were much lesser in those with moderate to marked bronchodilatrasane and also low CT finding of airway wall thickness in that purple line that we have. And then in terms of FEC, this is the most, I think, important useful one you can see, which is validated again from the new definition, that you can see those who had significant change in FEC had significant emphysema and air trapping in their CTs and PFTs. And also here it's kind of mixed again. Here it said all bronchodilator response FEC, sorry, those with moderate and high had higher St. John's respiratory quotients but fewer exacerbations and lower dyspnea scores. So it's kind of mixed again. In terms of looking at bronchodilator responsiveness over time, this was a subset of patients from SpiroMix with 40 to 80 years and 20-pack year history smoking. There were almost 2,300 patients. And they studied whether there was never bronchodilator response or inconsistent bronchodilator response or consistent. So what they've shown is compared to the ATS bronchodilator response or FEV1 or FEC, you can see that those with consistent are always having FEV1 decline over time compared to those who never had it. So you can see there's decrease in FEV1. And those with normal lung function, goal state zero, if you follow them over time, the consistent bronchodilator response had 10 times high likely of having progression to COPD. So this was good. Now, coming back to the confusion again, the COPD gene cohort study by Dr. Bhatt et al., who published this last year, showed that about 3,339 patients, it did not have a prognostic value in predicting exacerbation frequency and all-cause mortality. This was using the new ERS-ATS definitions. So they said there's a need for increased specificity in the bronchodilator response group. So in key points, about 30% to 50% of patients with COPD will have bronchodilator response. So having bronchodilator response does not indicate the clinical response to therapy. And the converse is also true. A greater bronchodilator response may correlate with worse asthma control. However, the study recently didn't show that. And from the COPD gene cohort, it did not have any prognostic value. So in summary, the usefulness of positive bronchodilator response in airway disease is still controversial. It doesn't distinguish asthma and COPD. We know that. It does not predict long-term bronchodilators. We know that. But we need future trials to validate and prognosticate and even find the utility of bronchodilator response. With that, I thank you. I'm happy to take any questions. Thank you so much, Dr. Decato. My name is Aaron Baugh. And I want to talk with you today about what we know and what we've learned about the use of race in spirometry. Now the first most important point is that we can't pick winners and losers. You might think I'm invoking this in a moral sense. And that's certainly true. It's not our role as physicians. But I actually want to stress that this is quite literal. If you look between the race-specific and race-neutral approaches, there is potential benefits to be seen in either side. And so our task has to be, both from a scientific and an ethical standpoint, a little bit more sophisticated in how we want to help people. So let's get into this. What is the problem with race? Well, unlike other designated determinants in our reference equations, it is neither objectively objective nor is it externally verifiable. Race is a very personal thing. And so while you can have things that are testable, like genetic ancestry, there's also elements that are entirely experiential, like your family history or past discrimination and how an individual weighs these different branches or elements that go into what they call their race is entirely idiosyncratic and you can't really predict it. And that gives us some trouble when we try to put this into an equation. So you might have heard, as I did when I was in medical school, that racial differences in mean spirometric function are about body proportion or anthropometrics. And we can correct for this by using sitting height. And I just want to point out that if that's the case, I have two different pictures here. One is looking at the sitting height correction and one is looking at race-specific equations. But these are two different pictures. And so how can it be two different pictures if they're supposed to be the same thing? What else is being adjusted for when we use a race-specific equation? You might say, well, Aaron, there's other things in body proportion besides just the sitting height. Maybe if you measure another dimension, other anthropometrics, you can capture it. And that's a really smart thought. It's also one that Dr. Jacobs had in 1992 when he used five different metrics of chest cavity size to try to capture what are these body proportionality differences between races and do they explain things well. He found that it only explained 22% of the racial differences between white and black patients. In fact, a recent systematic review from Holland et al that was published in Chest this year showed that even the upper bound of all studies that use these body proportion or anthropometric approaches only get us to about 37.1% of that racial difference, so not even half. And so really here, we're kind of confused. I don't have answers. But fortunately, this is not the first time that our profession has been without answers. And so it's not for nothing they call medicine both a science and an art. And since I can't give you a very factional answer here, I thought I could at least share with you some poetry. This is Paul Lawrence Dunbar. He was hailed as the first credible black poet on the national stage. After Phyllis Wheatley was hailed as the first credible black poet on the national stage in the time of George Washington and before Langston Hughes and the members of the Harlem Renaissance would be hailed as the first credible black poets on the national stage several decades later. I want to share with you a stanza from his poem, Sympathy. And it goes, I know why the caged bird sings, ah me, with winged bruise and bosom sore, when it beats its bars and would be free, tis not a carol of joy or glee, but a prayer sent from its heart's deepest core, but a plea, upwards to heaven he flings. Yes, I know why the caged bird sings. And that is probably the most famous poem you didn't know you knew and inspired Maya Angelou so much that she made it the title of her best-selling autobiography, Why the Caged Bird Sings. And if we were to think about, well, how would we analyze a poem like this? The first question you might ask is, well, what happened in that author's life to make him write the words that he did? And we could say that in the case of Dunbar, his parents were slaves. And so there was a very visible limitation that put on both their lives and his growing up in poverty. We could also consider that while other famous authors of his generation, like Rudyard Kipling and Mark Twain, were traveling the world as celebrities, he was stuck in the National Archives working in a dusty building behind barred windows, where that dust exacerbated a bout of tuberculosis, which would eventually kill him. If we were to ask the same questions of influence about pulmonary function, what might we find? Well, first we could try to take genetics out of the equation, like this study of 116 Japanese Americans, all with four Japanese grandparents. And so the only differences between are whether they grew up in the United States or primarily in Japan, which at the time of their childhood would have had a three times smaller GDP. And as you see, these different exposure patterns set them into a lung function growth pattern that has an apparently racial effect, right? Japanese or Caucasian reference equations do they fit to. Similarly, we could think about the case of Taiwan, which as it transformed from the island refuge of the losers of the Chinese Civil War and a resource poor land, into one of the five tigers of Asia and the world's largest economy, there was concurrently this increase in their lung function. So this is from Yang to VGH Healthcare. It happened concurrently with their GDP. And it's hard to say, well, that's all just a coincidence. Bringing things back closer to home, let's look at the case of Pinckney, Benton, Stewart, and Hinchback, the first elected black lieutenant governor in the United States. Now the interesting thing about him is by his appearance or by his ancestry, he was primarily a white man. But certainly by his life experience and his own self-identity, he was decidedly black. He was threatened with enslavement and had to flee several times. He was denied promotion in the army many times because of his race. And you saw what his sister told him. And these individuals, these mixed-race individuals in the Reconstruction era, make for us an interesting experiment. Because we have data from them, thanks to the large spirometry experiment done by Benjamin Gold of Civil War veterans. And so looking at the lung function of his reported mixed-race or as he would have said mulatto veterans, what we find is that in contrast to every single modern study that is based on the genetics of mixed-race people, their lung function does not fall in between the white and black, but here right on top of the black veterans. And that's really hard to make sense of until you can see that in that period of the Reconstruction, there was no difference. Mixed-race people, because of the single drop rule, were treated exactly the same as black people. And many of them were also enslaved, right? And so it seems that this social difference was more determinative of their lung function than the genetic difference. So what else could we do to analyze a poem? Well, we might think about the impact. What is the author trying to say to us? What does he want us to do? In Dunbar's case, he's talking about flinging a plea towards heaven. He wants us to think of higher things, not just focus on suffering. And I think that same thing is true when we think about race-neutral equations. There have been some theories about why there are decrements in lung function across different races, but that's not our focus, and nor is it our focus to call different people racist or whatever. But we want to think about the higher thing. How can we help everyone with these new discoveries? And so I want to point out that in my original work in spiromics among heavy smokers with at least 20 pack years, what I showed was not just that our black patients had a better correlation between their symptom burden and their lung function when using a race-neutral versus a race-specific approach, but also look at the regression line for our white patients or our white participants. It's also better. So the correlation is improved for both. I'm not sacrificing one to improve the other, but everyone can gain from this. Similarly, if we think about writ large all the other work that's been done in the last two or three years, we see that while race-specific approaches were meant to give us a clearer view of physiology, they've in fact obscured our view of things like asthma severity, all-cause mortality, and they've not given us any value prognostically for things like hospitalizations for lower respiratory disease or complications after doing a lobectomy for early-stage lung cancer, which is, you know, why you might want to do this. But on the other hand, I don't want to suggest to you that the answer is all solved and everything's perfect about race-neutral approaches either. Here's some serious problems. So we know from this recent study in gynecology surgery, we have the potential to double down on existing disparities in access to lung cancer resection. We know from the case of the cotton dust standards that this could give us potential disparities in hiring practices, and we don't want to expose people to unnecessary anxiety or testing or let alone treatment for falsely low values because we used the wrong reference equation. So I thank people for these questions, and I think we have a responsibility to answer them. Just looking at hiring to see what this is about, we can see in two different things. This is taking identical CVs or resumes and changing to a black or a white-sounding name. This is looking at department store hiring in the same location, same profitability, on whether there's a black or white manager. We see in both cases that black applicants are disadvantaged when they're not being hired by someone that's black, so when there's like a white manager in charge. And so this would be a real concern if we empowered this or doubled down on this tendency in professions where there's regular screening of spirometry. So I partnered with LifeScan Wellness. This is a safety company that does screening for 35 fire departments over the United States. We tested in 9,000 member firefighters and over 450 firefighting applicants in a single year applying the race-neutral approach according to current National Fire Protection Agency standards. And as you see in these two, and go back, as we see in these two, there's minimal loss of equity. I can only count on two hands the number of people who had a loss of their firefighting status based on these, right? And so that's one industry, but we deserve answers in the same kind of verification for every single one. This is beyond the stage of just conjecture. We owe it to people to get the verifiable answers. I want to thank you for listening to me today and letting me share some of my favorite poetry with you. Just to reflect, we spent some time talking about reconstruction-era figures like Paul Lawrence Dunbar and PBS Pinchback, and I think there's a lesson in their lives. The reconstruction era was a brilliant era with a lot of promise for equity and growth in the U.S. that we shrank away from just because people got tired of the conversation. So I beg you, whether you agree with me entirely or disagree vehemently, please don't get tired of this conversation. Help us fulfill the promise of this moment and find the factually, scientifically verifiable answers to how we should use race in spirometry. Thank you so much. All right. The title of my talk is How Do I Best Identify Obstruction by Spirometry? And that's where I work. So these are the objectives. And we do have a few audience response questions. So how is airflow obstruction currently defined? Well, the most recent ERS ATS technical standards define it the same way as the 2005 standards. It's an FEV1 to FEC ratio. It's less than a statistically defined lower limit normal, or the lower fifth percentile or negative 1.645Z scores. Now the difference between 2005 and 2022 is how the severity of impairment is graded with the current guideline statement using Z scores, a Z score of less than 2.5, absolute value is mild, 2.5 to 4 moderate, and more negative than 4 is severe. So first patient, 33-year-old male. And that's his flow volume curve and volume time curve. And I don't know if I can get the mouse to work, or right here. So that's working on my thing. But what is the, so what is that line, well, first of all, vital capacity is 123% of predicted scores, FEV1 is 104% of predicted, FEV1 to FEC is less than the lower limit of normal, negative 2.0Z scores. And so we know what happened here, the straight line. How do you make the mouse work? Oh, I have to use the laser, I'm sorry. So what we did here, you know what this is? So what our techs do is they do an on-the-fly quality control test. So anybody that has a value that's above the upper limit of normal, they put on a three-meter syringe and do a quality control test to make sure our flow sensor's working. So anyway, that's just an on-the-fly QC test, and our machine was working. So does this patient have airflow obstruction? Yes. Does his FEV1 to FEC ratio is less than the lower limit of normal? No. Well, he can't really have obstruction if his FEV1 is above 100% of predicted. And the third is, well, maybe, how about some clinical information? All right, yeah, so I think that's the right answer. So this patient, 33-year-old male, no symptoms, very fit and active, was pre-employment testing for the fire department. He also got bronchodilator, didn't show there was no change. So what are the choices here? Well, this could be mild obstruction or it could be what we call a normal physiologic variant, and that's defined as an FEV1 to FEC ratio less than the lower limit of normal with both FEV1 and FEC both 100% of predicted. And there's really two possibilities for this pattern. One is they have mild airflow obstruction, and two, they have a normal physiologic variant due to dyssynaptic lung growth. That's disproportionate growth between lung size and airway caliber. And I think the simplified way of viewing this is, you have a cylinder here with piston shooting air out, what would be equivalent to a conducting airway. So body capacity is more or less proportionate to the volume of this cylinder, and FEV1 is more or less proportionate. It's obviously oversimplified to this airway diameter. And you can easily see how, well, somebody just has more alveoli, larger lungs than they do conducting airways. So the normal physiologic variant, more common in younger males with tall stature. And a pattern was found in 4% of patients undergoing pre-employment spirometry in one study. They're evaluated with questionnaire, bronchodilator testing, methylcholine, single-breath nitrogen washout, and about 80% had obstructive abnormality, and 20% were thought to have normal physiologic variant. So why is this important? Well, meaningful interpretation requires additional information, evidence for airway hyperresponsiveness, air trapping, low DLCO, oscillometry would be useful, clinical information. And beware of the potential impact of a false positive interpretation of obstructive lung disease, especially in a person who is trying to start work in the fire department. So what about some of the alternative spirometric indices to identify obstruction? We have FEV1 over VC max. Remember, we get multiple vital capacities when we perform spirometry. We have the forced vital capacity. We have an inspiratory vital capacity. We have an inspiratory vital capacity when we do DLCO testing. And then we have a slow vital capacity when we perform lung volume testing. So the, and then there's FEV1 over FEV6, FEV3 over FVC, FEV3 over FEV6. So patient two, a 52-year-old male with 10-pack year smoking history and exertional dyspnea. I don't have Z-scores here. It's previous to our Z-score utilization. But just look at that PFT. So does this patient have airflow obstruction? Well, yes, the FEV1 divided by VC max is less than, I guess we should put in quotes, a lower limit of normal since we really don't have reference values for FEV1 over VC max. No, because the FEV1 over FVC is greater than the lower limit of normal. And well, it would have been yes from 2005 to 2021, but no in 2022. Okay. Yeah, I think that is the right answer, is three. So this patient, using a FVC, his FEV1 to FVC ratio is above the lower limit of normal, which is here, was 0.75. And the, that's, but you can see here, the FVC is less than the IVC performed with diffusing capacity. And here you can see the FVC met our criteria for end of forced exhalation. So it seemed to be a good study. Exhalation time was 10 seconds. So FEV1 over VC max was less than the lower limit of normal of 67.7, so suggesting mild obstruction. So in 2005, we were using FEV1 divided by VC max and that was preferred over FEV1 over FVC for identifying obstruction because, quote, it was capable of accurately identifying more obstructive patterns. So that's what we did from 2005 to 2021. And then in 2021 to 2022, the guideline statement says, well, FEV1 over VC max, it may be more sensitive, but it's not as specific and it will increase the uncertainty about the validity of the diagnosis, especially in the older population. Well, where does that come from? Well, here's a study in CHESS in 2019 where they looked at FEV1 over slow VC. There's some literature on the difference between FVC and slow VC, and FVC, or slow VC is greater than FVC as you get older and also in obesity and in patients with obstructive lung disease. But there's a low FEV1 SVC and a normal FEV1 FVC. Does that identify patients with clinically important airways disease? And the conclusion with that was, well, yes, if you were younger, if you were under age 60, or if you're obese, or if you had an FEV1 above 70% of predicted, but no, if you were greater than age 70, you had more false positives. Only 10% of the discordant patients, i.e. that had a low FEV1 SVC, but a normal FEV1 FVC, were diagnosed with airways disease in this study. So what about FEV1 FEV6? Well, the new guideline statement says, well, you can substitute, you can use FEV1 FEV6, can be substituted for FEV1 FVC for defining obstruction, and it's more reproducible, less physically demanding, and has similar sensitivity, multiple references. But you have to have defined lower limit of normal. So remember, in HANES-3, we did have a lower limit of normal for FEV1, FEV6, but GLI-12 does not. So if you use the GLI equations, which are currently recommended, you do not have a lower limit of normal. What about FEV3 FVC and FEV3 FEV6? So there's a whole body of literature on this, and it really provides a sensitive indicator of obstruction when the FEV1 FVC is normal. So those patients that have a low FEV3 FVC, or FEV3 FEV6, compared to ones that have, and have a normal FEV1 FVC, they have a lower FEV1, they have more symptoms, more dyspnea, more emphysema on CT, lower diffusion, more small airways disease, and a shorter six minute walk test. So this does identify an important group, where you're less than lower normal here, but above the lower limit of normal here. But once again, the same problem is, we do not have lower limits of normal for these parameters in GLI, we do for NHANES-3. So patient three, 86 year old female with dyspnea, sort of flow volume curve, volume time curve, didn't meet criteria for end of test, using the old scoring system, but regardless, it looks to be, exhalation time is about nine seconds. So the, you can see the FEV1 FVC ratio in the lower limit of normal. So does this patient have obstruction? Yes, the FEV1 to FVC is less than .7, and you could also say, boy, that shape of that flow volume curve sure suggests obstruction. No, the FEV1 to FVC is greater than the lower limit of normal, and their Z-score is negative 1.48. That'd be interesting to see what people think. No, yes. So this, well, first of all, this, Dr. Niven's gonna talk about PRISM, and you might call, say this patient has PRISM, and that they have a normal FVC, a normal FEV1 to FVC ratio, and an FEV1 that's less than the lower limit of normal. Well, people define PRISM in different ways, but we'll hear more about that upcoming. But, so this raises that GOLD versus ERS ATS definition of obstruction. And so GOLD, remember, defines obstruction as a post-bronchodilator FEV1 to FVC that's less than .7. And why do they use a fixed ratio? Well, it's simple, it's independent of reference values, and it's used in most therapeutic trials. So remember, this is the GOLD definition of obstruction. That's the way severity is graded. But the thing to remember is that the fixed ratio will result in under-diagnosis in younger patients and over-diagnosis in the elderly, because FEV1 decreases more than FVC as you age. So the ratio decreases. And so this is male predicted value. So somewhere in the, this is using NH3 values, but somewhere in the late 40s for males, the lower limit of normal for FEV1-FVC becomes less than .7. In fact, when you get to be 80, 90 years old, the predicted ratio is right around .7. And this just shows multiple studies that show the same thing, that this is just a study looking at ages 60 to 100, and this is the incidence rate of obstruction using the fixed ratio, and as you get older, the fixed ratio, the amount of obstruction markedly increases, where the lower limit of normal doesn't change much. Well, which one of these is best is the question. And the, so the fixed ratio approach, this is, Surya Bhatt in JAMA published this. He had four large U.S. general population cohorts, and age, I think the age was 45 to 100 or so, once again, 24,000 people, and they were followed for a minimum of 15 to 16 years. And they basically just said, well, what is the, which predicts the important COPD-related events, which were hospitalization and mortality? And they used this Harold C. statistic. So they looked at various fixed thresholds between .65 to .75 and compared it with a lower limit of normal, statistically defined lower limit of normal. And the fixed ratio threshold of .7 to .71, you can see here, was optimal at discriminating the, these important events. And so, but the fixed ratio threshold had a lower specificity, 79 versus 89, and a higher sensitivity. And in this population, I think roughly about 60% were current or ex-smokers, this general population study. 15% were defined, had obstruction defined using the lower limit of normal, and about 26% using a fixed ratio of .70. So this seems to suggest that maybe gold is not so far off base as we all state it is. So gold versus ERS definition of obstruction. So fixed ratio will definitely result in over-diagnosis of obstruction in the elderly. There's no two ways about that. And the concern is it's gonna result in over-treatment in the elderly. But I think we need to all remember that the diagnosis and treatment of COPD shouldn't be just based only on a FEV1 to FEC ratio. We should consider other clinical factors. And there's probably not much difference overall regarding prognosis between the two. All right, well thank you for your time. So last but certainly not least is Alex Niven from Mayo Clinic who is going to help us understand PRISM and the nonspecific pattern. Well thank you very much. Very, very impressed at this dedicated group turning out on a Wednesday morning in Hawaii to talk about pulmonary function testing. So my name's Alex Niven. I'm the co-director of the Pulmonary Function Lab at Mayo Clinic Rochester and I have nothing to disclose. So we're gonna talk a little bit about terminology because I think terminology in this area has been remarkably confusing over the course of the years. And see if we can anchor some of the terms that we use with regards to nonspecific pattern in PRISM with both patient-centered outcomes and postulated and current future directions to better define physiologic mechanisms. So I'd like to start with a case and I'm just curious. This is a group of experienced pulmonologists who interpret pulmonary function testing all the time. So I'd like you to interpret this case of a 65-year-old woman, former smoker. You can see her height and weight and BMI here. You can see the flow volume curve and the volume time curve on the right-hand side. This patient has lung volumes and an FEC that fall within the normal range, as you can see by Z-score. FEV1 is isolated reduced with no significant bronchodilator response with a ratio that falls above the lower limit of normal and a normal DLCO. So, got it? Got your interpretation? So how would you interpret this test? Is this unclassified, nonspecific PRISM obstruction or possible restriction? Vote early, vote often. All right, looks like we plateaued there. Thank you very much for that robust response. Nope, few more people keying in. So I'm really actually excited to see the answer here because there is no right answer to this question. And I think that the distribution of responses that we have here reflects that and also the confusion that I think we struggle with with these categories of patients. So in our lab, we would call this the nonspecific pattern, but that's largely because our old lab director, Bob Hyatt, described the nonspecific pattern. And so out of respect to him and his paper, we continue to do that. And just to anchor our discussion within the 2022 ATS-ERS interpretive strategies, what we're talking about here, at least what's listed in the guidelines, is an individual who has a normal FEV1-FEC ratio and an abnormal FEC falls into this possible restriction nonspecific pattern. And when we obtain lung volumes, those lung volumes are typically normal, the TLC at least. Now, the nonspecific pattern that Bob Hyatt first described back in CHEST in 2009, he defined as a patient who had a normal TLC pleth, a normal ratio, and either a low FEC, FEV1, or both. And in his study, but really in very few subsequent studies, he required that the DLCO should be normal. And looking at a large database of our patients, over 80,000 patients over the course of a long interval of time, he found an incidence of almost 10% of patients who fit this pattern. And there was actually quite a spread in terms of clinical diagnoses. A significant number of these patients had asthma, a significant number of these patients were also obese, and a significant number of these patients had both. Chronic lung disease was mostly COPD, and then there was a potpourri of different diagnoses that we would typically associate with physiologic restriction. Now, Vivek Iyer looked at a longitudinal cohort of our patients, a smaller cohort, almost 1,300 studies. He looked for individuals, again, using that same nonspecific diagnosis or nonspecific criteria that Bob Hyatt did, except he liberalized the definition to allow patients with low DLCOs. He also examined bronchodilator response, airways resistance, and a variety of other parameters listed here. Although his definition was really looking at any individual who had spirometry or repeat pulmonary function testing performed serially over the course of more than six months, the vast majority of patients in this study had a mean follow-up of three years. And what he found was a significant proportion of these patients actually remained nonspecific using this definition. Although there was a smaller but significant cohort that progressed to both restriction and obstruction, with a few reverting to normal and a few progressing to a mixed pattern. And interestingly, he found that there was really no significant difference in terms of the rate of FEV1 decline in the individuals who stayed nonspecific compared to the normal population in the lung health study. Now, that last conclusion may not be true. And I will spare you the considerable number of hours that I spent plowing through the PRISM literature, which is a really, really heterogeneous population of studies. And instead of giving you what really is a wide and disparate sort of data set, I'm gonna give you some summary statements from what I took away from that literature. So preserved ratio-impaired spirometry, which is, I think, increasingly the term that we use to apply to this nonspecific pattern that I've just described to you, is defined as either a reduced FEV1 or FEC or both with a preserved ratio. And when we look at all of the studies, we find that a lot of the patients who have this pattern are very similar to those original studies of the nonspecific pattern that I've described. It's seen more often in women, patients with an increased BMI. Smoking history is kind of variable in a variety of different studies, but diabetes is common. These patients have increased respiratory symptoms. They have increased difficulty with activities of daily living. They have worsening exercise capacity. Some individuals have looked at markers of systemic inflammation and found them to be increased. And this is probably the best and largest mortality study that I found posted on the right-hand side here. And you can see that the curves really start separating in about five years or so, suggesting that individuals with PRISM may have an increased rate of both all-cause or coronary heart disease or respiratory-related mortality over longer periods of time. So I'm gonna share with you just a few of my headaches as I plowed through this literature review. The challenge is that the incidence of PRISM is highly variable when you look at it in different clinical studies, ranging anywhere from three to 20%. And that's a real concern, especially because one of the key elements in the differential diagnosis with PRISM is poor performance of spirometry. And we all know the checkered history that we have clearly documented in literature in terms of how good we are at applying ATS standards to daily testing. Obviously, we've already talked about the fact that the definitions of PRISM in these studies vary significantly, FEV1, FEC, or both with that preserved ratio. Some people use pre-bronchodilator values, some people use post-bronchodilator values. And it's interesting, especially because of that concern for poor performance, that in some studies, they have described spirometry reverting to normal over half the time. So is this a real clinical entity or not? Well, Bob Hyatt, when he described this entity initially, was really the first to postulate the underlying physiologic mechanisms that may be driving it. And he suggested that perhaps there is something preventing patients from inflating all the way to TLC, either due to a thoracic or neuromuscular impairment, or maybe it's the body habitus of obesity that leads to a reduced lung volume at peak inspiration, or it has something to do with volume de-recruitment or early airway closure, leading to a symmetric reduction in flows in FEC and FEV1 over time. And you can see in his initial study, there was actually a significant proportion of obesity at all levels with a nonspecific pattern. So let's talk a little bit about that first. Oh, I'm sorry, before we go there, let's talk a little bit about performance. And I need to share with you a little bit of a dirty secret about our lab. So Bob Hyatt is largely recognized as the inventor of the flow volume loop, so it's really hard to argue with things that he's put into place in the lab. And so when I inherited the role of lab co-director, we were not routinely performing forced inspiratory maneuvers as part of our spirometry. And that's because Bob Hyatt said it was a waste of time. Because there is really no physiologic limitation to inspiratory flow other than effort, he really advocated only to do inspiratory maneuvers if there was concern about a central airway obstruction. Now, we've implemented inspiratory measurements since that time. I hope he's not rolling over in his grave. But one of the things that we wanted to do was look at our data again to ensure that since we were not measuring inspiratory vital capacities on a regular basis, and this is now part of the must criteria for the 2019 ATS standards, that we weren't missing a large degree of poor performance. So this was a small study that Rita Eggleston presented at ATS in May that just looked at 113 consecutive patients who had coached FIFC maneuvers. And in the interest of time, I'll simply say that we found that there was a slight reduced frequency, or a slight increased frequency of poor performance, but it was still pretty good. So there's probably an element of poor performance with PRISM, and certainly if you see this pattern in your lab, you should at least go back and take a look at the curves and make sure that acceptability and repeatability criteria are met. But this does really seem like a true entity. So let's talk a little bit about obesity. Now, we know that the reduced thoracic compliance that goes along with the obese patient leads to a reduction in the functional residual capacity, and potentially a little bit of, and as a result, lower resting lung volumes. But when we look at large studies, looking at the impact of FEC and FEV1 of this physiology, it's really quite small. So certainly the predicted values goes down a little bit based on the quartiles of BMI shown up here in the top right corner, but the absolute changes really range only between 100 and 150 cc's, even at relatively extreme cases of obesity. This is actually two images that I took from a really nice review that Matt Hegewald published a few years ago, highlighting the impact of lower FRC and early airways closure due to the heavy chest wall and anthropometric changes due to adiposity in the abdomen with obese patients. And in the exercise lab, we see all the time this rightward shift in the exercise tidal flow volume loops to a lower flow segment of the flow volume curve, which may explain, or may suggest increased upper airways resistance as part of the driver of exercise-induced dyspnea in these patients. And it's interesting, by the way, that some of the increased airways resistance that we see in patients with obesity can resolve with weight loss. So perhaps it's resting lower lung volumes and changes in small airways resistance that is causing us to see this prism or nonspecific pattern. Now, this is a summary of a beautiful summit at the University of Vermont that was published a few years ago here now, looking at some of the other things that we see in the lung due to obesity. Because certainly there are a variety of different studies that have suggested that adipocytes actually are responsible for a whole variety of inflammatory cytokines that perhaps lead to inflammatory small airways disease, separate and distinct from the physiologic changes that I've just described to you. And certainly there is great data out there to suggest that obese patients have an increased rate of asthma and even respiratory infections. And it's important to highlight that obesity in and of itself is a complex syndrome that is related to all sorts of different socioeconomic factors, environmental exposures, and causes things like diabetes and insulin resistance that in and of itself can cause significant physiologic impairment with the lungs. I'll just briefly say that when you look at the studies that have examined radiographic findings associated with prism, they're all over the map and not surprisingly are associated with thoracic deformities. Some varied degrees of obstructive lung disease findings and perhaps a little bit of pulmonary hypertension. So this is how I've sort of started thinking a lot about lung function in general. I think that we have to recognize the fact that there certainly are specific disease states, genetic disease states that may predispose individuals to have abnormal lung function or abnormal lung development. And this is drawn from a really beautiful discussion that was published in the New England Journal in 2015. I think we also have to recognize that the lungs are separate and distinct from other organs in the fact that it communicates with the outside world. And so as we go through the normal path of lung development in childhood, adolescence, and early adulthood, there are a lot of different factors that could potentially impact lung function, including nutrition, activity levels or lack thereof, environmental exposures and other trauma and things that occur over time. Certainly those same factors, many of them socioeconomic, also predispose individuals then to have obesity, metabolic syndrome, which in and of itself might impact lung function, and then the choices that we make in terms of smoking infections and asthma. So when we look at the normal, and I'll say that in air quotes, blue line, and the classic accelerated rate of lung decline that we're all used to thinking about with smoking and COPD, perhaps PRISM represents a group of individuals who have just grown up in a different environment with different risk factors and have made different choices. And over time, they may or may not cross the symptomatic threshold that represents true clinical lung disease that we must treat. I think that there's also an oversimplification in the literature in terms of lumping all of these different disease states based on a spirometry disease pattern. And I wonder if there really are three different phenotypes, an obstructive lung disease phenotype, a restrictive lung disease phenotype, and perhaps a metabolic phenotype where the lungs are basically the passive victims of the underlying systemic inflammation. And for me, what I'm not really sure is if we divide this state into different disease phenotypes and stratify it effectively, does this represent an earlier period of time where if we can intervene, we can return that patient to normal lung function or not? So in conclusion, the nonspecific pattern and PRISM are really just overlapping terms in a very confusing area in the literature. Again, the definition FEC, FEV1 are both reduced with a normal ratio and a normal TLC. It is associated with significant morbidity and mortality. And so I think this is an important area for further research. But I think as I spend more and more time thinking about pulmonary function testing, I'm less and less confident about what the lower limit of normal really is and how I necessarily interpret this absent of a careful clinical evaluation. So with that, I'll thank you very much.

pulmonary function test interpretation

bronchodilator responsiveness

obstructive lung disease

spirometry interpretation

race

genetic ancestry

PRISM

nonspecific pattern

physiologic mechanisms