All right, iPhone standard time says it's three o'clock, so I think in the interest of getting everyone done at four, we'll get started. My name is Carrie Quill, I'm from the University of Rochester, and thanks for coming to the session today. We're going to be talking about personalized approaches to COPD management. We were supposed to have four speakers today. We have one who is down for the count, so Dr. Make has agreed graciously to fill in for Dr. Hosri, so he's going to be giving two in a row, leading off with Dr. Hosri's presentation on pre-COPD and the need for recognition. Thank you, Carolyn. So I have to express thanks to Sammy for putting these slides together. So anything you don't like about the slides, I didn't do them. Anything you do like about the slides, tell Sammy. So Sammy came in two days ago, and unfortunately he developed a fever and didn't get better the first day. The second day he had a higher fever, he said, it's the worst I've ever felt with a respiratory infection. So it got better today, and today I said, well, are you sure you should come? He hasn't gotten tested for COVID, even if he did, I wouldn't believe the results. So he's not here, but unfortunately we have to fill in for him. So we're trying to fill in the best we can. So Sammy's main point here, and the reason he chose this is because there is new terms in the literature here, and the terms are very variable. You'll hear a ton of different terms to describe something that at least in terms of gold, and Darcy can tell us if it's in the CTS COPD recommendations, is pre-COPD. So it's a new disorder, and it's pre means it's not really COPD, but these other terms are thrown about in the literature that are on this slide, and in fact there's more terms than this. Let me get my pointer on again here. Oh, I can't get it on. Here we go. There's your pointer. Okay, hopefully you can see my pointer on the screen as well. And so here's some terms that have been thrown about in the literature, early COPD. Early, that means it's going to be COPD at some time. Well, we don't know that this disorder, as I've defined it on the last bullet here, pre-COPD, really always turns into COPD. So is it early COPD or not? And early, does that have anything to do with age, because that's the next on the list here. Mild COPD. Early, does early mean early in terms of age? Is it young COPD, because that's another possibility here, the third bullet. So these terms have been used to define something that's not COPD. But the preferred term now you will see, and this terminology keeps changing, and there's other terms I'll define here too as well, is pre-COPD. So what is pre-COPD? So as in this slide, it's people who do not have COPD. And forever, it seems, since gold started, and as Tom Petty and Gordon Snyder and our mentors have all told us, COPD means airflow limitation. So pre-COPD does not have airflow limitation. So what is COPD-ish about it? Well, it doesn't, again, always go to COPD. But what's COPD-ish about it is that in order to have pre-COPD, you need to have an exposure. And it could be environmental exposures of all sorts, and in the U.S., largely cigarette smoking. But some exposure causes lung problems. And what are the lung problems? It's one of three. On this slide, you'll see that it's either chronic either or chronic respiratory symptoms and or structural abnormalities. And how do you tell that? That's on CT scan. And or functional abnormalities. In function, there's different kinds of function. It could be pulmonary function, may not be airflow limitation on spirometry, could be functional limitation in terms of six-minute walk or cardiopulmonary exercise test, all sorts of functions. So it's a patient who has, for example, in the U.S., a cigarette smoker, but has normal spirometry without airflow limitation, but has some other things. So we're largely going to talk about what that is and what that means. Now if you go back in history a little further, you'll see a couple other terms that have been used in the past in the literature. One of them is non-obstructive chronic bronchitis. So that's chronic bronchitis, cough and sputum, we all know about in our patients with lots of different disorders. And Steve's in the first row. He says, well, it could be bronchiectasis. But anyway, that means chronic cough and sputum without airflow limitation. That's the non-obstructive. So do some patients with pre-COPD have non-obstructive chronic bronchitis? Yes. That term is used an increasing amount here, but it was first described in the mid-'60s by the Medical Research Council. And then one of the first iterations of the gold recommendations and strategy was gold zero, which means at the time, cough and sputum without airflow limitation, because the rationale in those two decades ago was that cough and sputum can precede the development of COPD. And when people recognize as a public health problem, you need to think about those patients because they can progress to COPD. So again, very confusing terminology. So a little difficult to see on this slide. I'm sorry, I didn't have time to rearrange it. You'll see on the left-hand side, there is the definition of pre-COPD and the definition of COPD on the right. And what's similar and different? Spirometry is different because in pre-COPD, you have a normal FE1-FEC ratio, which is defined as equal to 0.70 or greater. And in COPD, you have a low FE1-FEC of airflow limitation. Symptoms. Well, now the gold recommendations are that COPD is not just airflow limitation, but it's symptoms. And symptoms can also be present in pre-COPD, but don't have to be. If you have emphysema on CT scan, functional or structural abnormalities, emphysema on CT scan and no airflow limitation in a cigarette smoker with exposure, that can be pre-COPD. Do you need the structural abnormalities to fulfill the diagnosis of COPD? No, it's not a diagnostic criterion. So both kinds of patients may have symptoms. Both may have structural problems or functional problems, but they're really different in both these disorders. So what's the significance of pre-COPD? So Sammy likes this slide saying pre-COPD may go to COPD, but it doesn't have to be. But at the same time, as I'll show you, these patients are at a high risk, high risk for progression not only to COPD, but for mortality and morbidity, and they have symptoms. And the morbidity may be hospitalizations with a COPD exacerbation. Whoops. COPD exacerbation. I can't say that. They don't have COPD. So a COPD exacerbation-like thing, some kind of acute respiratory illness that winds them in the hospital could be an acute respiratory illness in a patient with pre-COPD. Maybe it's a pre-COPD exacerbation. I don't know. Something like that. So what's the big deal? So patients with chronic bronchitis, we know that that's been a different group of people, whether they have airflow limitation or not. They have worse quality of life than people that do not have cough and phlegm, reduced walk distance since the COPD gene we showed, and increased of these exacerbation-like events which may or may not wind them in the hospital. They also often are on medications. Whether or not they have airflow limitation, their doctors are smarter than we are. Their doctors just say, you have some symptoms, we'll put you on some medications and try and control it, whereas there's no real recommendations on how to treat these patients. We don't really know how to treat them yet. Well, what about patients who have pre-COPD, whether or not they have chronic bronchitis? They have abnormalities on CT scan. They have exacerbation rates similar to patients with more mild degrees of spirometric COPD, gold one and two, worse quality of life, and poor health status. And Sammy put together some of the data showing these. So pre-COPD is not a single patient. I mean, talk about personalized medicine. This is personalized medicine. These patients may or may not have CT abnormalities, may or may not have symptoms, may or may not have spirometry findings. They're all different from one another. So this is a slide that was taken from a paper by Milan Hind and some of the other investigators and representatives on the gold recommendation panel. And you know, I think gold is good at putting out these papers before they put out their final recommendations for the year to show you what's coming up and say then point to this literature. And they use this article and say, well, here's what pre-COPD is. We wrote about it. So again, here's symptoms in the blue, structure in the green, and in orange, function. So let's talk about symptoms. So Sammy put together some of this information to look at symptoms in patients who have non-airflow inundation. One of the studies I like the best is the Copenhagen City Study. Large population of patients in Copenhagen. They follow over time to see the natural history of various things, including lung disease. And after five and 15 years, 13% and 20% of patients who had a history of cigarette smoking but no airflow inundation developed airflow inundation, and they had an increased loss of FEV1. So it shows you that sometimes the disease progresses. Not always, though. It's not the majority of the patients, but it may progress, and that's what we're worried about. And once patients have COPD, they redefine as COPD, you know they have poor outcomes as well. Many other studies here show the same thing that I don't have time to go through. And what about function? Well, in the Loveless Study, and one I like best here, patients who did not have airflow inundation lost an average of 40 mLs per year in 18 months, and they had a 36-fold increase in developing Gold Stage 2 COPD over about four years. So again, these pre-COPD patients you see do progress and have more declines in lung function and more mortality. What about structure? This is a bunch of studies as well. One of the ones I like is the first one here, the Nelson Study, which was a study of lung cancer, of screening CT scans for lung cancer, and they found that people without airflow limitation they screened for lung cancer developed obstruction and follow-ups and had more emphysema over a longer period of time and developed more problems on structure. And these other structural problems in these other articles show that structural abnormalities have a higher mortality as well, not just symptoms, but higher mortality. So when thinking about pre-COPD and putting all these together, you see that there's a reason to find these patients, and one of the things we don't do is we're not very good at finding them, even if we don't do screening spirometry. We need to screen patients, do you have a history of cigarette smoking, even if you're not now, and ask them about symptoms, and think about obtaining CT scans, because again, that defines poor outcomes in the long term, even if they don't have defined COPD, even in pre-COPD patients. You're going to do that for looking for lung cancer, and there's other reasons. One of the issues, I think, in lung cancer screening CT scans is you send the patient to a radiologist. Well, I'm ordering a CT scan, why? For lung cancer. So the report is no lung cancer. Well, that's fine, but read something else. Tell me about the emphysema. Tell me about airway walls. Tell me about coronary recalcification. Tell me about osteoporosis and compression fractions of the vertebra. So there's more to read than CT scans for just lung cancer, if it's done for lung cancer screening. I hope that radiologists will look at this as well as pulmonologists in primary care, and think about giving us a comprehensive report about CT scans. So why do we need to recognize this disease? Again, the summary here, we want to try to decrease the mortality, which may be from cardiovascular disease, not just pulmonary disease. Decrease risk factors. That means stop smoking. Think about disease progression and follow these patients longitudinally, and figure out if there's ways to improve the quality of life. So there's a lot of treatment opportunities here. However, we can't really tell you which one of these to take advantage of. But some of them are sort of common sense, right? So if these are patients who have cigarette smoking, you want to double down on your efforts for smoking cessation. Now people say, well, you should tell everybody to stop smoking. But you can tell these patients, if they have more risk factors for progression and other abnormalities, it's more important than it might be in the run-of-the-mill patient. So maybe that's something to emphasize for these patients. Patient-centered, personalized care. Going to double down on smoking cessation in these patients. Do you want to immunize everybody? Sure, you should immunize everybody. Maybe more important to think about these patients and give them reason to get immunized and vaccinated. Again, with the anti-vaxxers that have popped up for COVID, that spread, I think, to other conditions too, including influenza, and now there's RSV. So personalized medicine by telling these patients the importance of them so that they don't get a respiratory infection and wind up in the hospital with immortality. And then the last bullet, there's a study called the Rethink. And Rethink actually was published, the results were published in the New England Journal of Medicine about six months ago, I think. Alon Highlands, a principal investigator, Fernando Martinez was one of the investigators. So in this population, a pre-COPD, what do we have to treat them with? Dual bronchodilators. Well, what are dual bronchodilators going to do? Improve lung function? Well, their lung function's not abnormal. Is it going to improve their shortness of breath? Well, maybe. Is it going to improve their structure abnormalities? Probably not. And in fact, their major outcome was a CAT score. So the CAT score and the other outcomes, the secondary outcomes they looked at were not improved with dual bronchodilators. But I think we need different medications. So I'm charging and we're charging the pharmaceutical industry to come up with different medications for these patients who have a lot of airway abnormalities as well as emphysema. What can you do that's maybe anti-inflammatory in the airway to try to prevent progression and reverse that in these patients? So I think we don't have the right medications yet. And hopefully there will be more studies to look at not just improving symptoms and structure but decreased mortality. So to end, Sammy's got this slide. The tallest mountain in the world is Mount Mauna Kea, which is 30,000 feet. And over half of it is above ground and half of it is below sea level. But I think that's similar to pre-COPD. I think more than half the patients are below ground and not identified yet. So our charge is to try to identify these patients and personalize medication for them. Thanks. I'm informed we'll do questions later. Do you want some water? Are you good? Yeah, I'm okay. Okay. So do you all have your ARS out? Do you have your phone? And can you answer questions? Because, you know, I used to ask questions, you know, from the podium. And then I realized that it was a HIPAA violation. Everybody knew what everybody else was answering. And that's why nobody answered. And I played this game. Simon says you've got to answer. It didn't work. But apps, everybody answers. So this is about, here's my disclosures. This is about race or abnormalities in COPD. And we're going to talk about pulmonary function mainly. And so the first question is, should race-predicted normal values be used when you're interpreting pulmonary function tests? And your answers, please. No, 75%. Yes, 25%. Close enough. So this is really a very controversial area. Again, you know, Sammy and I did not pick easy topics that we can thank our chair for giving us these hard topics. And it's certainly very controversial as well. And we ask you the question at the end. Oh, it's more like 50-50 now. And there's no right or wrong answer to these questions, which is why it's fine. Answer whatever you want. I usually have some other answer. I don't know. I'm busy playing on my phone or something. I don't know what the answer is. So that's okay too. But let's see how we can inform that. So there's a long history of using race-predicted and adjusted pulmonary function tests. And the previous recommendations were to use them. In fact, these issues date back to Thomas Jefferson. One of the review papers I read said Thomas Jefferson recognized this as an issue as well. And the differences are apparent between some racial and ethnic groups in some studies, but not others. It depends on the population. And I think even more today, you know, there's not a – how many races are there? Are people intermarried, intermixed, and you can't necessarily tell what race somebody is even if they self-identify? And NIH, if you're an NIH study, you have to self-identify what race you are, what race you think you are. Black individuals were always considered to have lower pulmonary function, somewhere between 8% and 15% lower than whites. And it was also true in Asians. And so the question is, is that correct? And what are the problems that we have encountered by doing that forever? So there are a lot of environmental and social influences on lung growth. This is a slide I like that looks at various times in somebody's life. The first blue on the left is before birth. And if parents smoked when the child was in utero, they'll have smaller lungs. Same thing in childhood in the yellow second bar there. If the parents smoke or if the child has respiratory infections, they may not achieve normal lung growth. In addition, if patients are younger people are deprived, if they don't have adequate nutrition, if they live in a poor area with a lot more air pollution next to a highway, they will have smaller lungs. So how does that affect the normal values that somebody achieves over life? Well, we really don't know that. We really don't know a lot about these early life events. There is a study now ongoing by the American Lung Association in our Airways Clinical Research Network that is enrolling patients between the ages of 25 and 35. And the patients we're picking from various socioeconomic classes, various education levels that these people have, whether they smoke or vape or live next to a highway or don't, to try to look at all these influences during early life and not early childhood and antinatal, but this is afterwards, what affects their normal development of the lungs to achieve their maximum lung capacity? Because we think that vaping and smoking and living near a highway and poor socioeconomics all affect that, but we need to learn more about it. And more important than race is probably these other environmental and social influences on someone as they are growing. So in the first paper, I'll use two COPD gene papers, not because they're the best, but because I know them the best because I'm involved in COPD gene, so I like to use them as examples. So the first one showed that the fixed ratio of FE1-FEC, as we use it, of 0.70, under-diagnoses COPD in patients who are self-identified as African Americans. And in COPD gene, we chose this study 15 years ago when we started, as we wanted one third of the patients to be self-identified African Americans, so we have a lot of those patients. So we found that patients that did not have COPD, of those patients, there were more non-COPD and African Americans. Seventy percent of our patients who did not have COPD in all these patients, we chose them only because they were cigarette smokers, not because they did or didn't have COPD. Of the patients who had non-COPD, 70 percent were African American, and only 49 percent of non-Hispanic whites had non-COPD. So why should African Americans have more non-COPD than patients who are non-Hispanic whites? No particular reason. The African Americans were younger, so you expect they might have less COPD. There were more current smokers that had a similar 12-year mortality. So the differences blur between the non-Hispanic whites and African Americans as self-identified once you look at these other outcomes, like mortality, a really important outcome, no difference in mortality. Then we matched patients for lots of characteristics, including age, sex, and current smoking, and we found that there was lower six-minute walk, more severe exacerbations, hospitalization, a higher BOSE score, and more deprivation in the patients who are self-identified as African Americans. Again, social and environmental influence is being important. On the top, let me see if I can get the pointer to work a second. There we go. In the top left, you can see gold zero. African Americans are the red bars. The blue bars are non-Hispanic whites. You can see there were more gold zero, that is, patients with pre-COPD than the African Americans, and there were less people who had PRISM or had gold one and more people who had PRISM. So the characteristics of these patients were really very different, even though there was no reason that they should be different in the population. But as you can see, the African Americans in the B panel here on the top right had much lower incomes. In addition, they had much lower education. This is some high school, and this is high school diploma. You can see that non-Hispanic whites had more education. And if we look at something called the area deprivation index, this is we knew where people lived. If we look at what the deprivation index was in that area, you can see African Americans here had the highest level of deprivation, suggesting that it's not race, it's other things that affect these patients, and put them into different categories of spirometry. We then looked at FEV1-FVC and FEV1-FVC ratio, and African Americans had an average of 310 mL lower FVC. Their FEV1 was lower, too, by 170 mLs, but because the FVC was more low than the FEV1, the ratio was higher. So African Americans had a higher FEV1-FVC ratio, which is why they weren't diagnosed with COPD as much. The next study, we said that we looked at race-specific predictions that underestimate the severity of people that actually do have COPD. Race-specific predicted pulmonary functions underestimate disease severity, particularly in the pre-COPD and the prison patients again. And all these things may lead to delayed recognition of problems in African Americans if we use spirometry as our criteria for diagnosis of lung disease, and delayed treatment. So in the African Americans on the right panel here, in panel B, complicated slide. Gold zero is blue, for example, and we used lots of different kinds of prediction factors. So NHANES National Health Survey in the United States has race-specific, for African Americans, race-specific pulmonary function. If we use that, more patients had gold zero. That's the pre-COPD, and less people had significant grades of COPD. If we used GLI, other or global, the two columns here, this and this column, you can see there are less people that are diagnosed as pre-COPD and more people that had COPD. So again, changing your prediction formula has really changed how you interpret these patients and where they sit in their pulmonary function. There are lots of other studies too that have nothing to do necessarily with what I talked about in terms of gold staging. So the one recent paper I really found interesting was using race-specific predicted pulmonary function to show it's better lung function, not just better lung function, but worse correlation with other outcomes we think are important, like quality of life as measured by the COPD assessment test or the St. George respiratory questionnaire. The second bullet, race-neutral predicted values, neutral predicted values in NHANES and COPD gene, reclassified up to 20 percent of black patients into more severe COPD spirometry stages and improved the model fit with dyspnea and CT abnormalities. Race-specific, the third bullet, predicted pulmonary function yields a lower lung allocation score. So using race-specific pulmonary function may prevent people from receiving lung transplants. And the last one, race-specific pulmonary function is associated with poorer survival in African Americans, but that difference was lessened if you used race-neutral pulmonary function. So therefore, what we're suggesting here is the second bullet, clinical interpretation of pulmonary function tests really needs to change. And the suggestion by the ATS, the ERS, and multiple other organizations is that you need to treat each patient as an individual, and pulmonary function is not necessarily the most important thing to classify a patient and look at as a characteristic of patients who have COPD. Think about those other outcomes you talked about before for pre-COPD. Symptoms, lung structure abnormalities, progression, mortality, those are important too. Pulmonary function is not the be-all and end-all of COPD. Pulmonary function is only one characterization of the disease, so interpret pulmonary functions cautiously in individuals and don't treat patients based on pulmonary function alone. And I think recently all the recommendations have now gone along with this. So what do we do instead? Well, use race-neutral predicted pulmonary values. Where are they? So there's something called the Global Lung Initiative that has normal values. People know about GLI, Global Lung Initiative? Okay, really important. And there's not, I think, increased recognition of GLI would really be important. So this is a collaborative network of investigators around the world. It was established in 2008, and they wanted to collate existing cross-sectional data from all the countries together and all the patients in the world to come up with normal values. They ended up with almost 100,000 asymptomatic lifelong non-smoking people in 33 countries centered in these areas, white, North Asian, Southeast Asian, African-Americans, age, big age span between 2 1⁄2 and 95 years, over half were female, and there were different data sets. And so there are data sets for each of these populations, white, African-American, Southeast Asian, and North Asian, but the suggestion is to use the comparison of all the patients together. Don't race-predict them. Use race-neutral equations. And although I'm not going to go through this, this algorithm was recently published in Chess. This is a suggestion about what to do. You measure lung function, and you calculate based on age, sex, and height. No race here. And look at the PFT report and the measured variable, and then rather than looking at the numbers, look at the pattern. Does it look more like airflow limitation? Does it look like restrictive disease? It's the most important thing to look at first rather than look at the individual numbers. And then think about what additional assessments you need, as I discussed in the last talk, maybe structural issues, CT scans, symptoms, other function like diffusing capacity as well, and think about how you want to classify those people. So my questions didn't get in here, but my last question that's not in here is, will you now use race-neutral pulmonary function tests, normal values, when you interpret pulmonary function in your institution? And I hope that the answer is everybody is saying yes. And the data set you use for normal values is from the GLI normal values. Thank you. Okay. We're right on time again. I'm Carrie Quill from the University of Rochester. I'm going to talk today about the role of sex and gender in COPD. I have no relevant disclosures. And my objectives today are fourfold. The first thing I want to do is to make sure we're all speaking the same language. So we're going to start with a couple of definitions. Then I'm going to review some of the historical and contemporary epidemiology of COPD as it relates to sex and gender. And then we're going to talk about the impact of biological sex in COPD. And at the end, we're going to start to delve into the impact of gender and gender identity in COPD. So just a few things to get into today. So to start, it turns out that COPD is a great disease to explore through the lens of sex and gender. Needless to say, the interplay is complex. And for some of you in the audience, this stuff is like kind of duh, right? Like you're like, okay, like go, or like let's go, like come on, I'm ready. But for those of you for whom these are newer concepts, just to make sure we're all saying the same thing, sex, when I talk about sex today, I'm talking about biological characteristics, anatomy, physiology, reproductive organs related to chromosomal sex at birth. In contrast, gender is a social construct which potentially informs exposures, study populations, diagnostic and therapeutic biases. Gender identities are non-binary. So thinking about COPD in history. So historically, COPD was really considered a disease of men and the prevalence in the early 20th century was substantially higher among men owing to temporal trends in smoking. As a result, a lot of our medical education and the information that were presented is steeped in images of men with COPD. So you have this classic picture of the blue bloater and the pink puffer, which are almost universally male. The classic fish or peto, or flesh or peto curve also first described was derived entirely from data from male smokers. So we sort of have in our brain that COPD is a male disease. But in the US, smoking really took off among women in the 50s, 60s and 70s. And these are really shocking advertisements to review kind of back in time. And this resulted in a dramatic increase in the diagnosis of COPD beginning in 1980. I don't think this is quite what Virginia Slims had in mind when they said you've come a long way, baby, but I don't know. So is this winning? So it turns out that the age adjusted prevalence of COPD among women has been consistently higher than that among men since the turn of the century. So since the year 2000. If you look at age adjusted death rate in the bottom graph there, they changed the colors around. So just be mindful of that. But the age adjusted death rate has been consistently declining among men and has been pretty steady among women since that time. Furthermore, women in the younger age group 45 to 64 are 51% more likely than men of the same age to have COPD. And this drops to 21% more likely when you compare women and men over 65 years of age. So obviously we're gonna start by talking about sex. So for those of you who haven't read this little ditty, it's 116 pages. It could pass a lot of time on the flight home. You'll know the three months it took between submission and reading, that's how long it took to read the paper. But this is sort of the original study that looked at the differences in lung function between females and males. So among other things, Hutchinson in this paper measured the vital capacity of over 2,000 males from a variety of sources, very colorful and in today's language, not appropriate in his description. And he compared them to the vital capacity of 26 girls. What he found was that regardless of height, females have a lower vital capacity than males. His interpretation of this finding was not based so much in data, so much as it was based in some very gendered thoughts. He concluded that the heaving of a woman's chest is very perceptible even when in her full attire. There you have it. Several years later though, Dr. Ellis concluded that women have less need of air than men finding the same thing. So you have this sex-based finding that is interpreted in an incredibly gendered way. So the basics, what we know about lung physiology, difference between females and males is that the male lung is larger than the female lung in persons of similar height, and males have greater lung capacity and flow volumes. What are the implications of this? So this is probably the best study that looks at the impact of smoking comparing females and males. So this was an analysis of 150,000 females and 100,000 males in the UK Biobank. And they took patients who they had data on spirometry, smoking history, and anthropometric data, and they looked at the association between smoking and sex. And the study conclusively showed that for a given amount of smoking exposure, females were far more likely than males to develop airflow obstruction. This is consistent with a number of additional observational studies that showed that females developed COPD at a younger age compared to males when exposed to equivalent amounts of tobacco smoke. There also is some role of female hormones on lung function. This is a nice review of some of these roles. And the implication of this is a little bit uncertain at this point, but I just wanna briefly review some of the roles of female sex hormones in the lungs. So estrogen is known to promote TH2 response, whereas androgens promote TH1 response. And this may obviously have some relevance in management of both asthma and COPD. It's thought that progesterone may augment airways inflammation, which again is potentially a modifiable area. And then finally, and this is something new that I learned while preparing for this talk, cigarette smoke is metabolized through phase one and two enzymes, and estrogen may potentially upregulate that phase one enzyme, leading to accumulation of toxic metabolites via bioactivation. So that is really fascinating to me. So to review the biology, here's what we know. Females develop more severe COPD at a younger age than men and with lower levels of cigarette exposure. Among males and females with similar severity of COPD, females had fewer packers of cigarette smoke exposure. And female smokers have a faster annual rate of FEV1 decline compared to male smokers. What about gender? This is where things get a little bit more sticky. So gender often, but not always interacts with sex and the manifestation, diagnosis and treatment of disease. And the two areas I wanna focus on today are the way that gender plays a role in the disease of COPD have to do with diagnostic bias and seeking of care and then exposure. So as I mentioned previously, much of our early understanding of COPD was as a male disease. Around the same time that females began to overtake males, this study was published in 2001. And what they sought to do was to investigate the role that gender plays in physician diagnosis of COPD. This is a really elegant study. So this was published in 2001. They studied 192 primary care physicians in the US and Canada. And they presented the physicians with a hypothetical case presentation of a patient with cough and dyspnea and a smoker. And there were six different versions of the case that differed only in terms of age and sex. After presentation, the physicians were asked to state what they thought was the most likely diagnosis and then choose appropriate diagnostic testing. Then they were given some spirometry results and again asked the most likely diagnosis. What did they find? So what they found was that women were far less likely to receive a provisional diagnosis of COPD based on the case presentation. Once they had the objective data, this difference was attenuated and was no longer statistically significant. But the problem is only 21% of physicians ordered spirometry based on the initial case presentation. There are several subsequent studies that show that women are less likely to receive subspecialty referral and are less likely to receive guideline-based care compared to men. And this is sort of something that has come up frequently in the literature and is not a sex-based difference but rather a gender-based difference. The second example of course is biomass exposure. So in case you don't know what biomass is, everybody's heard of it, right? But like what literally is it? I just have the variety of things that are burned that are listed for you. But shocking to remember that 50% of all households worldwide, including some households in the Southeastern United States, and 90% of rural households use biomass fuel as their main source of energy. Biomass smoke constituents include small particulate matter, which is a problem. And the PM10 levels in homes using biomass fuel are up to 70 times above ambient levels of the most polluted cities in the world. And who does the cooking? It's the ladies. So girls and women typically start cooking around the age of 15 and will spend four to six hours per day in the kitchen, usually in an enclosed space with poor ventilation. Over the course of a lifetime, women are exposed to biomass smoke for up to 30 to 40 years with a cumulative exposure of 60,000 hours. And this is a massive problem. We know pretty clearly that biomass exposure is a major risk factor to COPD. And it turns out that it's actually almost, the odds ratio of developing COPD is essentially akin to the odds ratio, risk associated with cigarette smoking. And indoor air pollution is really among the top preventable risk factors causing disease in developing countries. So this is an area of huge concern. And again, is a gender-based area of difference in COPD. Three billion people currently are exposed to biomass smoke worldwide compared to 1.1 billion smokers. So biomass smoke is probably the biggest risk factor for COPD globally and gets very little attention here in the United States because it doesn't affect us. But I think something really important to be aware of as sort of like awake and aware pulmonologists. There's also a lot of data on symptom differences between females and males, or is it men and women? And I think that a lot of these symptom differences sit at the intersection between sex and gender. So you may have heard described this female phenotype. And this like raises the hair on the back of my neck a little bit. So people describe more severe dyspnea, more cough, more mental health problems, lower quality of life, more severe anxiety and depression, all of these things theoretically controlled for FEV1, age, pack years, et cetera. So I have sort of collated a couple of the studies that looked at dyspnea, consistently showed that women report higher dyspnea than males with similar FEV1. And also higher rates of anxiety and depression. I think it's really important to read and know this data, but my suspicion is that a lot of this data and these differences between men and women are driven by both sex and gender. For example, a gender bias in referral, diagnosis and treatment will likely influence patient reporting and perception of symptoms. And gender roles might find women more forthcoming about symptoms of anxiety and depression. So just be mindful in attributing these differences to biology alone. I think it's more complicated than that. I wanna end just with an eye on the future. Currently in the United States alone, there are 1.6 million adults in the US who identify as transgender. And interestingly, transgender youth are three to four times more likely to use e-cigs or tobacco cigarettes than their cisgendered counterparts. And it's really important to determine, a lot like we were just talking about in the racial issues, it's really important to understand the best way to interpret lung function testing of transgender non-binary patients. This is an incredibly marginalized patient population with poor access to care and poor health outcomes. So this is another opportunity to really advocate for this patient population. So the major unanswered question for this population is what is the appropriate reference range? Should we be using birth sex? Should we use gender identity? What's the role of gender affirming hormone therapy? There's no standard age of initiation and clearly the timing is gonna matter. So for example, if you start gender affirming hormone therapy during early puberty versus after completion of puberty, it may have a significant impact on lung function and lung development. The current ATS recommendation is to use birth sex, but this is incompletely executed in practice. And this is a really nice review from the Annals of ATS published this year that really looks at the varied proposed solution and kind of goes through some of the pros and cons of each of these. I'm not gonna walk through this, but I think this is a really nice overview. And I think more will be revealed in this realm, but what I would encourage all of you to do is to be cautious and sensitive in these interpretations and to be really explicit in your documentation about what reference range you chose and potentially why you chose it. So in conclusion, developing personalized strategies to treat individuals with COPD requires us to understand the distinction between sex and gender. There may be some biological sort of sex-based targets for precision medicine in the future, but right now we can elevate our care for people with COPD by increasing our awareness of gender bias in the diagnosis, treatment, and study of COPD. Thank you. And then last, we have our resident Canadian, Dr. Marciniak here to talk to us about BMI as a disease modulator in COPD. Not sure how to get the pointer on, but we'll do without it. Or Barry, thanks so much. So first of all, thank you very much to the chairs and to the organizing. Very much appreciate the opportunity to be with you this afternoon. And actually a special call out for Barry who did Sammy's presentation very short notice and did a great job. So thank you very much, Barry. And who's also a resident IT expert here as well. Didn't work, sorry. Oh, thank you. We'll go fine here. So my task today is to speak about the relationship, the association between BMI and all that that means and COPD. This is my conflict of interest disclosure. I do work with health systems and provincial governments and healthcare delivery systems. I don't receive honorary or any sort of interactions with ad boards and so forth with pharmaceutical. So what I hope to do is for all of us to appreciate how obesity affects and influences respiratory physiology in COPD. In doing so, they understand the relationship, potential consequences, understanding between BMI and also fat-free mass. Our understanding of its impact, how it affects performance symptoms and outcomes and so forth is growing in COPD. And then we'll talk a little bit about practical approaches and interventions. Some of that is hope. There's not a lot of literature yet that utilizes what we know into practice, but I think we do have some learnings that will positively help our patients with COPD across the spectrum of BMI and nutritional status. So a lot of obesity out in the world. So the data that I've referenced here is about 10 years old when we started to get really excited about it. And at that time, the prevalence is about 25% of patients with COPD are obese. And now our overall population, depending where we are, may be as high as 40%, but much higher obesity in patients with COPD versus those with not, about 50% higher. We know that obesity specifically in COPD is associated with poorer health-related quality of life and increased healthcare utilization. But it's also associated with better exercise performance. I'm gonna show you a little bit about that. So there's a, that's a trade-off in terms of what we know and what we've learned. And then there's also concurrent or comorbid conditions such as diabetes that is about also 50% more likely, more common in COPD. When we look at patients that have more severe or very severe COPD compared to individuals without COPD. So these are kind of just what we're living now and it is evolving and it doesn't seem to be going away. In fact, it's probably getting worse. This is data that Dennis Adorno published in about, geez, 12 years ago now. And on the upright axis is lung volumes as a percent of TLC. The first group is normal. And you can see three colors, red being the residual volume, yellow being the expiratory reserve volume, and blue being the expiratory capacity. And then as you move over, gold one, gold two, and gold three and four. Mild, moderate, severe, very severe. Each of those have four bars, underweight, normal weight, overweight, and obese. Underweight would be a BMI less than 20, normal would be 20 to 25, overweight 25 to 30, and over 30 is obese. And for normal, these were age-matched healthy nonsmokers. What you can see is with increasing BMI for gold one, gold two, and gold three, four, that there are consistent reductions. That is less hyperinflation, less gas trapping with increasing BMI. That is to say, if you look at, for instance, gold three and four on the far right, the red goes down when we go from underweight, normal weight, overweight to obese as the disease progresses, despite disease severity. So that's an independent factor for lung volume. So we know in COPD that hyperinflation gas trapping is bad. So if you are overweight or obese with bad lung function, you have less gas trapping. That's a good thing. And there's consistent data since then that has demonstrated this. Let's look at this a little bit closer. Here you have comparisons. Again, this was out of Dennis's laboratory published in 2009. Individuals with COPD, FEV1, about 49% are predicted. So their age and severity of obstruction matched. Normal weight, you have the residual volume, the ERV, the IC, and the obese, RV, ERV, IC. So you can see there's less gas trapping. And in fact, total lung capacity is less as well. So all the volumes have shifted down a little bit. What does that mean for exercise performance? And again, a pointer would really help here. But what you can see in the middle, if we look at the orange, that's the overweight population. The greenish is the normal weight. Both of them have COPD of similar severity. The volumes in the normal weight are higher. But you can also see that they don't exercise as long as the overweight COPD patients. And in fact, end expired lung volume, that's at the bottom of those shaded either peach or green colors, was lower at rest and during exercise for obese than it was for the normal weight. And again, this is a BMI of 22 versus a BMI of 35. So patients who are obese, similar degree of obstruction, reach an end expired lung volume at end exercise that was in fact lower than the normal weight. So not only can they go longer, exercise longer, they also had a higher peak ventilation because of less gas trapping. So in this case, in this specific instance, obesity is a good thing. Why? Well, on the left, vertical axis is dyspnea, reported as board score. So it goes up from 0 to 10. In this case, it goes up to 8. Over minute ventilation from 0 to 50. So let's just concentrate on the left. And I've highlighted where it matters in green. The open squares are normal weight. The dark black closed are the obese. If we match ventilation at 25 liters, and you can see that arrow, patients who are obese have a modified board score mean of 1.2. And the normal weight is double that at about 2.4. So for a given ventilation, all else being equal except weight, normal weight have more shortness of breath. On the right, we look at why. Again, dyspnea, board score on the vertical axis, but inspiratory reserve volume expressed as a percent of TLC on the horizontal axis. And you can see that dyspnea goes up for both of them as IRV goes almost at TLC, 5%, 10%, 15% working backwards. And the normal weight people are on a steeper part of the curve, higher inflection, closer to TLC. And we know that that's associated with increased dyspnea. So we've documented that normal weight have more shortness of breath. We've documented that their volumes are not as advantageous as when you're obese. And we now know why, because they're closer to TLC. And that represents our ceiling when we're exercised. Nobody likes to breathe very close to TLC because that's a constraint. So that's kind of in the laboratory. What about in populations? So lately, there's been some analysis of big studies. There's a summit trial published in 2016. These were people with COPD enriched with cardiac risk factors, about 16,000, I think, in total. And here, you can see on the vertical axis is hazard ratio of mortality, dying. And that line that's drawn across is corrected for normal weight. And as we work from left to right, we have BMI less than 20, then normal, 20 to 25, 25 to 30, 30 to 35, 35 to 40, and so forth. And there's kind of a U-shaped risk with mortality. So there's that association between BMI, mortality in a population with moderate COPD, heightened CV risk, confirming that all-cause mortality is associated. Now, this is not cause and effect. But it's associated higher and underweight, the first part of the U. And then now, this study actually, for the first time, said in the very obese, BMI greater than 40, there was also increased mortality. And we're going to look at why that might occur. But also learning from this, mortality was actually less in the overweight and the mildly obese people for COPD, again, confirming what we know from smaller studies. This is a big trial, 16,000 people. TioSPR, which was 17,000 people, three-year trial, patients with COPD. Some were given teotropium by one device, two different doses, another with another device to see if there were any difference. And what they've, they showed a very similar findings. The top, and I've identified in blue, the top is all-cause mortality. The middle is respiratory death. And the bottom blue is cardiovascular death. And to the right represents a higher risk. And to the left is a lower risk. And again, you can see at the top, if we just look at all-cause mortality, there's kind of a U, but it doesn't reach significance for all-cause mortality in the very obese. In the middle, underweight have an increased risk of respiratory death, not so much in the overweight and the mild, moderate, and significantly obese. But the cardiovascular death also has that U, although it's just turned on its side. So underweight and overweight. Overweight still touches zero, so it's not statistically significant, but there's a trend that starts to maybe help us understand why that might be the case. It's beginning to look like it may not be related to the respiratory etiology, but the cardiovascular consequences of significant obesity. And here, being underweight with COPD in multiple measures is not a good thing, not only for exercise, but also for outcomes such as mortality. What about hospitalization? Much smaller data set, 301 patients. This is published in 2020. Hospitalized for COPD and exacerbation, survived, went home. And at the time, their length of stay, time to clinical stability, outcomes at hospital were the same, but followed for one year afterwards. And the obese are in the darker squares, bars. The non-obese are in the lighter squares. And I've put numbers in red that identify kind of what those values are. So in hospital, they go home, 30 days, no real difference. But at six months, non-obese, non-obese have a higher mortality, 18 versus seven, statistically significant. And at one year, non-obese have a higher mortality, 28% versus 8%. So patients with obesity had a significantly lower death at six months and also at one year. Again, this is just watching. It's not cause and effect, but it raises some interesting questions. So that's just BMI, but our understanding of BMI and things like that in other fields is growing, and it's not probably the best indicator. What about fat-free mass? So here we have data that looks at the fat-free mass, and there's various ways to estimate that, to calculate it. Your wristwatch can give you a number about what your fat-free mass is, and if I do that, I get a number I don't like. So I think it's not very accurate. There's more accurate ways to do it. But here I've shown on a normal individual, an obese, a pre-obese, which is just mild, and then normal weight, and then underweight. And you can see in this population, this was published this year in TREST, that the proportion of fat-free, red being as low fat-free mass, blue being expected fat-free mass, and gray being high, fat-free mass is very low in the underweight, as you would expect, and less also not what you would expect in normal weight COPD patients, compared to pre-obese and obese people whose proportion of fat-free mass is more like you would expect in a normal population without COPD. So that's also something that goes into the mix. And then when we look at it a different way, this is a six-minute walk distance, so an outcome measure, activity, underweight, normal weight, pre-obese, obese, you can see that fat-free mass correlated with six-minute walk distance in the underweight and normal weight COPD patients. And those people had the lowest proportion of fat-free mass, but no correlation in pre-obese and obese because they seemed, I think, to have the higher proportion of fat-free mass, normal, similar to a normal individual in spite of or despite their obesity. So the pre-obese and obese patients had a higher fat-free mass, and it was not associated with better exercise capacity in difference to normal weight COPDers and underweight COPDers. And then this data just looks at how that might be best estimated. Lots of data here, too small to read. But at the bottom are six-minute walk test data, and you can sort of creeping up to the right. When you see dots to the right, that means there's the highest correlation between outcome and the ability to distinguish that outcome, discriminate the outcome, and fat-free mass. So at the bottom is the incremental shuttle walk test, not much data. Six-minute walk test, quite a few dots, and some of it shows, some of it doesn't, and then you have cardiopulmonary exercise testing. And where the ones to the farthest right are looking at peak VO2, aerobic capacity, and peak power output, PPO. And in fact, the association, the ability to distinguish, to understand the relationship, the outcome of fat-free mass and outcomes, is best with peak VO2 and peak power, which is readily available on cardiopulmonary exercise testing. So more detailed physiologic allows us to better understand that. And so I think what we're seeing now is some work, some research to try and understand what this is, and then eventually take that, so now that we know this, what can we do? But we can't forget about other COPD comorbidities, and other comorbidities associated with obesity. So metabolic syndrome, osteoporosis, skeletal muscle dysfunction, cardiovascular disease, respiratory diseases, are all higher in patients with COPD than they are in the normal population. So we're not just dealing with obesity, and we're often not just dealing with obesity and COPD, there's many other concurrent or comorbid conditions. So, tough to know what to do. So we know, however, that there's an increased mortality risk in patients with COPD who are underweight. We do not want our patients with COPD to be underweight, just if we look at something like hospitalizations, and exercise performance, and mortality. And we now know that there's also, from big cohort studies, that extreme obesity, BMI greater than 40 is also that, and it's likely attributable to cardiovascular reasons. There seems to be a protective association in overweight and moderate obesity in terms of exercise performance and mortality risk, and we say that in the exercise laboratory. And it needs to be better understood, and is it only just because of mechanics, and is it because of the contribution, the fat-free mass that is more like normal than those who are underweight? And then also in underweight and normal weight patients, a higher fat-free mass index is consistently associated with better exercise performance, and we don't know yet if it has other positive benefits or not. That still hasn't been studied in large numbers. The numbers in this are pretty small. There is a positive association between fat-free mass and exercise capacity and COPD. That kind of makes sense. And the higher the fat-free mass, the higher the peak VO2 aerobic capacity. That's a good thing. The higher the fat-free mass, the higher peak work rate, and the six minute walk distance. So those are also good things. So what do we do? What are some of the practical considerations? Well, I think we can never forget, let's actively optimize and manage our patients with COPD, and that begins with pharmacologic, non-pharmacologic behavioral interventions, system changes that kind of benefit our patients. That has huge impact, even when we're concentrating and thinking about some of these smaller things. I think given what we know about fitness, about fat-free mass, and such, there's even more reasons, more understanding why pulmonary rehabilitation works. And it's not like we need more reasons, but we need more pulmonary rehabilitation. Our patients with COPD have to be able to realize the benefits of exercise reconditioning, aerobic strength exercise training, maintenance, goal-directed, supervised, and so forth. And I think we also need a greater nutritional appreciation and understanding. And so sometimes in our call to get rid of obesity and to normalize weight, we may be a bit misdirected sometimes in terms of our guidance. So that BMI-driven nutritional supplementation and weight loss intervention may not, and we don't know for sure, but it may not be entirely right. We do know that consistent evidence, very consistent about being underweight is not good. And there's reasons why they're underweight, and some of the interventions today in the literature have not been very successful in terms of affecting the weight and or affecting the outcome. So more work needs to be there. But in the meantime, we can work with what we know and what we've learned. And then finally, I'd just say stay alert because there's a lot of work being done in the area, and so I'm sure that there'll be more findings that'll help inform our practices and our understanding in the area. Thank you very much. Thank you.

obesity

BMI

fat-free mass

COPD management

exercise performance

gas trapping

comorbidities

underweight

mortality

nutrition