Good morning, everyone. Nice to see you here. Thank you so much for attending this morning. This is a session that we are all of us are really passionate about, so we're very excited that you're here and have that passion with us. Our topic is women and lung disease, sex distinct care. I'm Anita Rajagopal. I'll be the chair this morning. Joining me is Dr. Glassberg, Dr. Lam, and Dr. Levine. We'll be starting with catamenial disease, then Lam, followed by pulmonary hypertension, and ending with obstructive lung disease. This is just my intro slide. I serve as a network medical director at Community Health Network in Indianapolis. I have nothing to disclose, the objectives. Just go ahead and get started with some background. I know it's been a while since we've had our OB-GYN rotation, but what we're talking about is endometriosis. Endometriosis is defined as the presence of ectopic endometrial tissue, so the stroma and glands outside of the uterine cavity. It's estimated to affect about 6 to 10% of reproductive-aged women, although it's thought that the incidence is actually much higher, so it's something that we do need to be aware of. Among this population, 12% are estimated to experience endometriosis of non-reproductive organs, referred to as extragenital endometriosis. The most common site of endometriosis outside of the abdominal pelvic cavity is within thoracic cavity. Thoracic endometriosis syndrome includes catamenial pneumothorax, hemothorax, hemoptysis, and pulmonary nodules. I'll be referring to that as TES today. TES is considered to be a manifestation of endometriosis progression. It's evidenced through observations demonstrating an older age of onset and coexisting pelvic endometriosis in women with thoracic endometriosis. The mean presentation is typically 25 to 30-year-olds for patients with only pelvic endometriosis. When you look at patients with thoracic endometriosis, that mean goes up to about 35 years of age. Patients typically experience symptoms of pelvic endometriosis approximately five to seven years before developing symptoms of thoracic endometriosis. Now thoracic disease can occur in isolation. However, it's usually associated with extensive endometriosis of reproductive, GU, and GI systems. So now, the symptoms can range throughout there. So reproductive, you may have a patient who has trouble with infertility. GI, there may be pain with urination. There may be pain with bowel movements as well. So those are just little things to keep an eye out on. Pathophysiology, there are a few different theories out there. So we don't know exactly how this occurs, why this occurs, but there are quite a few theories that have been put out. The most popular one is Samson's theory. Samson's theory is a theory of retrograde menstruation. So what this is proposing is that endometrial cells undergo retrograde movement through the fallopian tubes into the peritoneal cavity. There they implant onto peritoneal surfaces. There's then circulation of peritoneal fluid containing these endometrial cells that follows a distinct pattern. So this pattern is that it flows from the pelvis through the right pericolic gutter to the right hemidiaphragm. I know this is a lot, but this is actually important. Because what this does is it deviates away from the left hemidiaphragm due to obstruction of flow from the thalassoform and phrenicolic ligaments. Upon reaching the right subdiaphragmatic area, endometrial cells are thought to then implant on diaphragmatic surface or undergo transperitoneal transdiaphragmatic migration to the pleural cavity via congenital or acquired fenestrations within the diaphragm. So what this means is that endometriosis is nine times more likely to occur on the right hemidiaphragm versus the left. This is just a picture that shows you what this looks like on the diaphragm. Another theory I'll mention is the metaplasia theory. This hypothesizes that endometriosis arises by metaplasia of mesothelial cells lining the pleura and peritoneal surfaces into endometrial glands and stroma. The problem with this theory is that it fails to explain bronchopulmonary lesions or the right-sided predominance that's seen in most cases. Another theory is the benign metastasis theory. This proposes that implants are the result of lymphatic or dissemination of endometrial cells. The last theory is the prostaglandin theory. This theory hypothesizes that circulating prostaglandin increases with menstruation, which then leads to constriction of bronchioles and blood vessels, which can lead to alveolar rupture of previously formed subpleural blebs and bulla, resulting in a pattern of catamenial pneumothorax. We talk about clinical manifestations. This can be very variable. A lot of patients can be asymptomatic, which makes this even trickier. The symptoms of thoracic endometriosis are largely related to the anatomic location of the lesions. So it can typically present with symptoms of catamenial pneumothorax and chest or shoulder pain. Catamenial pneumothorax is defined as recurrent pneumothorax occurring within 72 hours of menstruation. It's the most common clinical manifestation of thoracic endometriosis occurring in 72 to 73% of patients. The symptoms experienced by patients are comparable to those of spontaneous pneumothorax, which we know. Heredic chest pain, cough, shortness of breath. Diaphragmatic irritation may produce referred pain. So this is one thing to look out for. This kind of sets it apart from other spontaneous pneumothoraces, where you get referred pain in the periscopular region or radiation to the neck. Oftentimes this pain is specifically on the right side. So a patient may say, I've been having this strange shoulder pain, very sharp, not really sure why it's there. It could be from irritation from the diaphragm. Again, the right hemithorax is involved in up to 92% of cases, with 5% of cases involving the left hemithorax and only 3% experiencing bilateral involvement. Catamenial hemothorax is a less common manifestation. Similar to catamenial pneumothorax, it presents with nonspecific symptoms as well. Cough, shortness of breath, heredic chest pain, again, predominantly on the right side. There are rare cases of left-sided hemothorax that have been reported. Less common would be bronchopulmonary TES. This presents as mild to moderate catamenial hemoptysis. Massive life-threatening hemoptysis is rare. Pulmonary nodules actually can be fine, but we know we see that in many things, right? But it can be an incidental finding at the time of imaging or it can occur in symptomatic patients. These vary in size, typically smaller, 0.5 to 3 centimeters. Because clinical manifestations can be variable and an association with menstruation is not always recognized, you really have to have a high clinical suspicion in order to have a timely diagnosis. So some things just to keep an eye out for would be the relationship with menses, predominantly right-sided symptoms, young age, presence of recurrent disease, and a history of infertility. Those can give you clues that this might be what's going on. When we look at diagnosis, despite low specificity, actually the most sensitive tests for detection of pneumothorax and hemothorax are chest X-ray and CT, whereas MRI is preferable for the diagnosis of diaphragmatic endometriosis. It has a reported sensitivity of 78 to 83%. Pneumothoraces on chest X-ray or CT can be of any size, again, typically right-sided, about 88 to 100% of patients. Also may result in shifting of the mediastinum. Other signs that may be present would be pneumomediastinum, pneumoperitoneum, ground glass opacities, bronchial wall thickening, thin-walled cavities, bullous, of course. I brought this slide because this is actually an important slide. So when you look at the imaging, typically what we look at as pulmonologists is we're going to see this massive pneumothorax, right? A lot of times what may actually be missed, I know when you look at it this way, it's like, how could this be missed? But if you think about the typical chest X-ray, it's going to come up a little bit higher. So you only see part of the diaphragm, right? So a lot of times, things like this just might not be noticed. But if you look at what I've circled, that is actually part of the liver herniating through. So the liver is herniating through fenestrations or just little defects along the diaphragm. That is a big clue. So that's what it looks like intraoperatively, if you look intraoperatively at what the liver looks like coming through. The other thing for diagnosis would be the gold standard would be the video laparoscopy as well as VATS. The largest review of patients with catamenial pneumothorax, 52.1% were diagnosed with thoracic endometriosis based on VATS findings. Most commonly reported intraoperative findings include diaphragmatic lesions, endometriosis of visceral pleura, discrete lesions such as bulla, blebs, or scarring. And 8.5% had no findings. So routine evaluation of the abdominal side of the diaphragm should be performed in all patients undergoing VL for suspected pelvic endometriosis. A lot of times, it's really difficult to do that because of the liver. So in order to improve the view, the surgeon, and you should also team up with somebody who is specialized and understands what they're looking for with endometriosis, so you want to have a good gynecological surgeon but as well as somebody who is a good thoracic surgeon familiar with endometriosis. There are different techniques out there. One technique that I found that was very interesting that's most commonly used is to put the patient in Trendelenburg and use a retractor to kind of push things forward with the liver, caudally, so that you can actually see everything to make sure you're not missing anything. This is another picture to show what endometriotic implants look like. Typically, they're black, blue, or have that reddish-purplish appearance. However, again, really important to know what else is out there. So there are clear vesicular lesions that do exist. So the surgeon may go in and say, oh, I didn't see anything blue, I didn't see anything purple, it's not endometriosis. Well, it might be clear, it might be white, so these are things also to be aware of. We all want to know about bronchoscopy, right? So bronchoscopy, biopsies, washings, those are going to be limited due to the propensity of endometrial implants to more light peripherally instead of in the mucosa of the large bronchi. In cases of bronchopulmonary endometriosis, brush cytology has been reported to be superior compared with using directed biopsies. Overall, though, diagnostic imaging and tissue sampling have inconsistent results. The performance of diagnostic imaging and sampling could be improved if you perform them at the time of menses and then compare them with imaging performed mid-cycle because you could see documented findings could disappear. So that is something that could increase your suspicion for TES. You want to do that comparison. For those who like pathology, this is what this would look like on H&E. So if you have suspicion and you have a specimen, you want to look for something that shows glands and stroma. CD10 also would be positive for this. Now how do we manage this? So for medical management, the first line would be to suppress the ovarian steroid hormone production. How do we do that? So gonadotropin-releasing hormone analogs are going to be first line. Those are highly effective in suppressing the access and growth of endometrial cells, but there are downsides to using those medications, such as menopausal-like symptoms, as well as osteoporosis. So other alternatives are typically used, which would be oral contraceptives, progestins. There's actually no change or difference in efficacy between these medications. Now there is a big caution with this. So if you start a patient on this and things seem like they're going well, the patient wants to get pregnant or wants to come off medication for some reason, just be aware that when you pull the patient off of any of these suppressive therapies, there's a high rate of recurrence. In those patients, you can consider using surgery for that or for recurrent disease. When we look at surgery, VATS is the gold standard for diagnosis and treatment, most notably for catamenial pneumothorax. The VATS procedure allows for multiple treatment modalities. That's going to be dependent on where the lesions are and the characteristics of it, but the surgeon can laser things away or they might just need to use sharp dissection. Sometimes these procedures can be a little bit bigger and there may need to be wedge resection or in some cases, lobectomy. Recurrence is going to be the most common complication. Unfortunately, recurrence occurs in 8 to 40% of patients at a mean follow-up of four years. The high recurrence rate exceeds those, of course, of idiopathic pneumothorax. An alternative would be pleurodesis. This can be accomplished chemically with talc or tetracycline or mechanically with pleural abrasion and partial pleurectomy. The use of pleurodesis was only demonstrated to allow a median recurrence-free interval of 61 months in 28 patients. It was reported to decrease the recurrence rate of pneumothorax after VATS by 20 to 25% compared to those patients who did not have pleurodesis performed at the time of surgery. An additional option to consider in an older patient or a patient who does not desire to preserve their fertility would be bilateral salpingo-oophorectomy with or without hysterectomy. This approach, though, does not address dormant endometrial implants that may be active even following estrogen administration. Just in some conclusions, even though it's rare, this can be incapacitating for many patients. That's something you really want to be aware of. Oftentimes, these patients may have gone to gynecology and had some sort of treatment options there, but they may end up with us through the ER or for other reasons. So it's something to really be aware of, especially with little things like, oh, my shoulder is hurting, oh, I was noticing some pain, some shortness of breath. This could be what we're seeing. Given the variability, you really have to have high clinical suspicion. The earlier you catch this, the earlier you can start them on treatment. In cases in which hormonal suppression has been exhausted, surgical management may be your ideal pathway. And again, hormonal suppression may reduce the risk of recurrence. Thank you. And I'd like to welcome Dr. Glasberg. We'll hold questions until the end. Thank you so much for organizing this great session. I know how much work this is, and we all appreciate it. So now we're going to move to a very cool disease called lymphangiolyomyomatosis, cool because it looks a little bit like Swiss cheese as we look at the CT scan on the right. And this is me. And the objectives that we're going to do is try to understand this heterogeneous presentation so that we all get good at recognizing it, understand the CT really clear as we look forward to more AI usage in this scan so that we can pick this up potentially earlier and sort of what our resorts are to treating this at the present time. So let's start with a case and talk about what's the most common presentation of this disease. And I'm going to call it LAM. As my kids say, if you say lymphangiolyomyomatosis 10 times, your tongue is going to get stuck. So we're going to call it LAM. So this is a 30-year-old woman who runs marathons and has no prior medical history. She noticed shortness, mild shortness of breath over the past two years, and she presented with acute shortness of breath. So this is her scan that she gets in the emergency room. And I think we can all recognize what's going on here is a very large pneumothorax. But also notice the Swiss cheese, right? So it's not in the setting of a normal lung that drops or lots of lymph nodes or anything else that you're seeing. What you're seeing is a really aggressive cystic lung disease that then presents as a pneumothorax. Is it going to play it again? It looks like it might. Well, you've seen it once. You've seen it enough. Okay. Let's see if we can get through. So this is the plain film. And we're going to talk about other options in these patients, like what else happens to them. So they can come with pneumothoraces. And the second most common one is pleural effusions. So this is a 49-year-old woman with no past medical history or trauma, presented with increasing shortness of breath and noted to have a large left pleural effusion. This is in the emergency room. She then goes out, and she has a series of thoracenteses, because she keeps presenting with recurrent pleural effusions, of which they are chylous multiple times. So you're all saying to yourself, gee, that's not so usual, right? We might see this as a perineumonic effusion or something. But these are chylous without any problem. But she has three separate ones. Nobody entertains the diagnosis. And then, let's see if I get this right. Okay. And this is now her CT scan, if the technology's going to work. There we go. So now you see the left large pleural effusion. And then you're also going to see cysts, right, that are smaller this time, right? They're smaller. But the lung certainly isn't normal, right? And this is after the second recurrence, this scan. There are a couple of ways these are managed. You know, people used to think you could ligate the thoracic duct, that that was connected to this. You could try octreotide, although there's not been a definitive study for it. But the treatment of choice now is serolimus, which we'll go through when we talk about the MILES trial. But this is her now after three months of treatment with serolimus at our center. The effusion has resolved. And you'll see she has no recurrence. She remains on this now. This is 10 years later, the scan that I'm showing you, with normal PFTs last week. And note that this is the current CT, and the cysts have also decreased in size. This always doesn't happen. So this is a lucky case. But here's an example, and we're going to talk about how does that management work? What's the science behind the management that actually has led to this very positive result? They all don't work like this. But it's important for you to have the tools of serolimus to be able to use it. This is the pathology of LAM. It's classic. It's got... Let's see if the arrow will work. No. Okay. So it's islands of muscle cells. And you see these very large pink bundles. And then you see clearance of the areas where the cysts are. But you see the pockets, the round areas of these cells. And what these things do is cluster. So when you grow them in the lab, they do the same thing. They talk to each other, and they get into these bundles. And so when you're biopsying these lungs, which is not done for diagnosis, but can be done at the time that a chest tube is put in, you will see this clustering and clearing. It's really architecturally interesting how it works. Because there's still normal lung mixed in with these pockets of cells. So these are now considered to be a low-grade neoplasm, right? They have a lot of the characteristics of a cancerous process. Not treated, though, yet with any other chemotherapy other than serolimus. So where are we? First description of this was in 1937. I've included the reference at the end of the talk. Where it was described as muscular cirrhosis of the lung. Why was that? Because they saw this pathology. They saw this pooling of these cells. So what have we learned? We've learned that this is a disease almost exclusively of women that has a worldwide prevalence of between 3.4 to 7.8 women per million. You know, in the United States, it's about 200,000 women a year that are totally diagnosed with this. It's manifested as progressive shortness of breath leading to respiratory failure, predominantly in Caucasians, not reported very much in African-American populations, but reported in Asians, not reported to date in American Indian. Pre- and post-menopausal occurrence has a different clinical course, classified, as I've mentioned, as a low-grade neoplasm and a member of the Pacoma family. I'm going to show you another interesting case in a minute about how a diagnosis was made through the abdominal biopsy of a lesion that led to recognizing the Pacoma. And two forms, cystic lung disease, so-called sporadic LAM, and then those that are in conjunction with mutations in patients with tuberous sclerosis, about 46 percent of those women will develop cystic lung disease, and that's called TSC LAM. It can also involve other organs. They can develop angiomyolipomas that sit on top of the kidney, and you should always scan them to see if they have those. And then constitutive activation of the rapamycin, the mTOR pathway, is what led to being able to use sirolimus because it blocks that pathway. Let me talk a little bit more about the Pacoma story so we know what that stands for. So these are pulmonary epithelial tumors. They actually start at the level of the epithelium, even though we recognize that the cells and the staining of the cell is for smooth muscle. Its relationship to tuberous sclerosis is about 27 percent of these patients have a mutation in TSC1 that's on chromosome 9q34 and encodes a protein named hammerton, and the rest of them, 73 percent, will have a mutation in TSC2 on chromosome 16p13.3 that encodes tuberin, sorry, vice versa on the slide. Rare cases have shown amplification of AKT2. We're going to look at this pathway because what you're seeing is that the possibility of how you get holes in your lung can actually be happening at several parts of the mTOR pathway. It's very cool. We don't know why these mutations occur, but it can happen all the way through it now. We've learned a lot of this in the last five years. Both of these proteins inhibit the mammalian target of rapamycin, mTOR, and what mTOR does is responsible for cell signaling and growth. So if you have a defective mTOR1 kinase inhibition, then mTOR1 is activated, and that's how this cascade starts. So this is this pathway. I won't spend tons of time on this, but you can start to see all the different areas that you could have a problem, and you recognize this. Here's the TSC1, whoops, TSC1, TSC2 story here, but as I mentioned, you can have mutations in AKT here and the subcomponents of AKT. So how does the rapamune come in is it's actually blocking here. mTOR1 is shown to you with the line here, and it can block mTOR2. But what happens is in some of the drugs, it does a better job blocking here than it does at mTOR2. So these patients will not have curative therapy because the cells are so smart, they can go around them. So the newer generations of the rapamune can antagonize both mTOR1 and mTOR2, and that's really where we're going. But you can see that this is a pretty complicated cascade, right, where the cell could come up with a lot of different mutations and probably we can get a whole. We don't know this though yet, so a lot of work needs to be done looking at scans, looking at the genetic profiling of the patients, and really using AI and machine learning to be able to recognize the depth of which mutations cause what and what the pattern, how the patterns are different based on the mutation. This is stuff we don't know. So what's the problem here? The problem for these women is the need for earlier recognition. So here's a 50-year-old previously healthy woman ex-smoker. She undergoes removal of a retroperitoneal fairly large mass, 12 by 4 by 2, a cystic mass, and a 3 by 2 by 1 intact non-viscous filled cyst in November of 2020. The pathologist labels this as a cystic perivascular epithelioid cell tumor, PECOMA, and writes in the report, the cyst is lined by benign malarian-type serous-like epithelium with subepithelial sheets of spindled cells, no overt features of malignancy. Several studies show PAX8, estrogen receptor, desmin, HMB45 are positive, melan A, patchy, and negative for DOG1. This is very classic for lymphangial myelomatosis, right? HMB45 has been the go-to for a long time as well in A. And these are sort of pre-melanosome markers suggesting that these cells are early in their development and they go awry. But this, nowhere in here do you see lymphangial myelomatosis. In fact, you see benign. Deeper sections are done. They're also, but interestingly, they're HMB45 and melan A negative. The surgeon decides to send this biopsy to Foundation Medicine for next generation sequencing, NGS, which identifies a mutation in tuberin, but it doesn't get included in the medical record. This is happening at a lot of institutions. So you get information you need, but you don't even know you need it. Say you're the third doctor coming into the case. You don't see the report. So you don't know this. So on follow-up imaging, she has evidence of recurrence. She goes back to surgery again. They take out another pacoma. So December 2022, larger mass on CT. She undergoes the resection, pretty big, 6x5x8. This time there's some lymph nodes that the surgeon notes and samples and reads out lymphangial myelomatosis. The patient develops chyluria. They don't recognize that as part of the pacoma problem. And the urologist comes in and doesn't recognize it and performs betadine installation to the left ureter. Chyluria gets better, but there's still no relationship to LAM, and she's not referred to the pulmonologist or to the LAM clinic. The first CT of this patient's chest is done in 2023, just about a month ago. And she has small cysts that I'm going to show you and less than four centimeter nodules with scattered punctate calcified granulomas, probably environmental. And the case was published previously without the CT of the chest in 2022 in a pathology journal. So I bring you this case to say, be aware. Delayed diagnosis has resulted in delayed treatment for this woman since she's just been started on sirolimus now, when she came to the LAM clinic at Loyola. So the genetic testing for TSC and VEGFD is still pending. The initial pacoma does, as I said, show a splice mutation in TSC, too, which is interesting. A lot of these patients don't have any manifestations of tuberous sclerosis. They don't have seizures. They don't have leaf-like lesions. They aren't mentally retarded. These are active, working women. So you have to question the penetration, sort of, of the mutation and what the clinical presentation is. So this is her CT. And you have to look really closely, but she's got some very tiny cysts. And so they're very, very small. They're scattered throughout. But she has lymphangial lymphatosis. So the MILES trial, which was a really seminal trial conducted by Frank McCormick and associates out of Cincinnati, led to the use of sirolimus. This is now, the mechanism of this is inhibiting mTOR, and we all understand that pathway. Patients have stabilized FEV1 decline, improvement of quality of life. What is the ideal dosing? We don't know because of the trial design. So there's a problem with how much you give them. A lot of the patients can't tolerate the drug. Clinical response is very variable. Some patients do well, as I showed you. The cysts get smaller. All kinds of things happen. Other patients just get all the side effects and don't do well. Importantly, the lung function declines when you stop the treatment. So you must keep the patients on the treatment. Remission is not induced. It's only a suppressive management. And what's being used now, as I mentioned to you, are drugs that attack mTORC1 and mTORC2. So both sides of the pathway using the next generation of rapamycin. So this is the trial just showing you the FEV1 differences between the top line, which is sirolimus, and the bottom, the placebo. Clearly, although you might question how much of a difference in the FEV1, this was a winning trial because there was a significance that was statistically valid. We ask, how much does the patient actually sense from this? It's interesting. Some patients think there's a big difference when they're on the sirolimus. But there's, once again, as I told you, the clinical response, they say there's no difference and they stop the drug. So in summary, look for LAM. Tell your surgical colleagues that when they get these interesting biopsies and they're not sure, they send it to functional genomics to call us, that we're interested. Many cystic lung disease are present, but remember the characteristics of the LAM cysts on imaging. There's no preference for any region in the lung. The size, as you saw when I showed you the first slide, is all over the place. It's very characteristic. The biggest confusing scan that you'll see is patients with Sjogren's syndrome. They will have big cysts, small cysts scattered through, but remember they will also, should have the markers of Sjogren's as well, which these patients do not have. Obtain the confirmatory studies and address the genetic screening and counseling. Although this is not a familial disease, it's important for us to identify what TSC defects they may have. And treatment is suppressive, so you have to really be, inform your patient that they need to be on the drug. The advocacy of this disease is abundant. These LAM foundation centers are all over the place and more are growing. These are good places to refer the patients and keep them off the LISTSERV. The LISTSERV can be really dangerous and promote, I think, a lot of depression, whereas at these centers they get a lot of information. So these are some references. This is a two-part series that we put together, a group of us, last year. That actually the first one, the senior people did, and then the second one actually has a bunch of fellows that helped write the paper. And we've been trying to promote these. If any of you in the audience have an interest in working together as sort of a mentorship group to write some papers for CHEST in this area, we are particularly interested in having you join us and help us. And then these are the classic papers, the Van Stozel paper from 37, very good review from Gene Sullivan that still is excellent, and then a more recent review from the Gupta group at Cincinnati that sort of talks about practice guidelines. And I'll stop. Thank you. Okay, great. All right. Well, thank you so much for organizing this great session. This is really a pleasure to be here, Anita. We'll switch gears a little bit and talk about the pulmonary vasculature and the cardiopulmonary axis in the setting of pulmonary hypertension, or pH. My disclosures. So many of you in the room will probably know that pH entails a heterogeneous group of diseases that are all characterized by a mean pulmonary artery pressure of 20 millimeters of mercury or more. We currently have five major groups. We have five major groups. The first one is PAH or pulmonary arterial hypertension. These are some of the most severe forms of pulmonary hypertension, and these forms are also amenable to a medical treatment. Group two is pH due to any type of left heart disease. Group three, pH due to any type of chronic lung disease or chronic hypoxemia. Group four is chronic thromboembolic pulmonary hypertension. And then group five is a hodgepodge of diseases with unclear and or multifactorial mechanisms. And histologically, the disease is characterized by narrowing or occlusion of the lumen of the pulmonary vasculature, which is caused by intimal fibrosis due to endothelial cell apoptosis and proliferation. There's medial hypertrophy with smooth muscle cell hypertrophy, as well as inflammatory cell recruitment, fibroblast proliferation, disruption of the extracellular matrix, as well as some other things, which then in concert lead to severe pulmonary vascular remodeling. And in the most severe types of the disease, again, this is PAH, pulmonary arterial hypertension. Patients develop these plexiform lesions that completely occlude the vascular lumen in a fashion that's actually very similar to malignancies. And it doesn't take a lot of imagination to imagine that it will be very hard for the right ventricle to pump blood in the pulmonary vascular bed that looks like this. So why do we talk about sex and gender differences in PAH and PAH, and why is this important for women? This here is another iteration of the five pulmonary hypertension groups. You can see this is very busy. But what I did here, I just wanted to highlight in yellow sexual dimorphisms that have been identified in various pulmonary hypertension subtypes. Again, I'm not going too much into detail, but the big themes that have emerged here is that women are more prone to developing PAH, and that gender difference exists in disease metrics as well as treatment responses and outcomes. And importantly, women with PAH and other types of PAH exhibit more favorable hemodynamics, better RB function, and better survival. So let's look at these things in more detail. This here is the initial publication that identified pulmonary arterial hypertension by Dressdale from 1951. And interestingly, all three patients that were reported were women. And we have since then learned in registries from all across the world that PAH indeed is a sexually dimorphic disease with a female-to-male ratio anywhere between 2 to 1 and 4 to 1. So this then raises the question, why is PAH sexually dimorphic and female-predominant? And there has been a significant body of literature that has been published over the last 15 years or so that indicates that estrogens actually can be drivers of pulmonary artery remodeling. And the themes that have emerged here is that 17-beta-estradiol, or E2, levels correlate with worse outcomes. E2 may increase proliferation of pulmonary artery smooth muscle cells and decrease BMPA2 signaling in these cells. It may increase, I'm sorry, aromatase, the enzyme that is responsible for making estradiol is actually increased in the pulmonary vasculature. And then there's a substantial body of literature that has shown that there is an estrogen metabolite called 16-alpha-hydroxyestrone, which can exert pro-mitogenic and pro-inflammatory effects on the pulmonary vasculature. So that's the estrogen part of the story. And then recently, we have learned that there might also be some genetic differences. And specifically, genes that are encoded on the Y chromosome may be protective. And there was a really cool paper published in the American Journal of Respiratory Critical Care Medicine just last year, where the authors showed that there's a gene on the Y chromosome called UTY, which may exert anti-inflammatory effects. So it's a pretty cool story. What the authors did here, they took a male mice and knocked down this UTY gene. And when they did that in a couple of different approaches, they found that these mice exhibit more pronounced pulmonary vascular disease. And the full story essentially is that if you don't have UTY, so either if you're a male or female, or if you are a male in which UTY has been knocked down or knocked out, this leads to a pro-inflammatory environment with increased expression of CXL9 and 10 and other chemokines, which then lead to macrophage infiltration and endothelial cell dysfunction and development of pulmonary vascular disease. It's a really cool new concept of looking at sex differences in pulmonary vascular disease. OK, so this is disease susceptibility. What about disease severity? There are also significant sexual dimorphisms. This is a paper from Corey Bentitullo that was published last year. Corey looked at more than 6,600 participants of subjects that participated in the major randomized clinical trials of PAH medications. And what Corey found was that male patients, shown here in blue, as compared to female patients, shown here in this pink-slash-salmon color, exhibit a higher six-minute walk distance. And this is adjusted for height. And then interestingly, in the female patients, but not in the male patients, this relationship was actually modified by body mass index. And when looking at hemodynamics, Corey found that male patients exhibit higher right atrial pressures, higher mean pulmonary atrial pressures, and lower cardiac indices. PVR was pretty much the same between the two sexes. And then the relationship with pulmonary wedge pressure was all over the place. But clearly, higher right atrial pressure, pulmonary artery pressure, and lower cardiac index in the male subjects. There are also gender differences in treatment responses. This here is a study that was published more than 10 years ago now. And here we learned that female PAH patients are more responsive to treatment with endothelial receptor antagonists. This is a trial, or this is an analysis that looked at six randomized placebo-controlled trials of various endothelial receptor antagonists. And you can see that the increase in six-minute walk distance from baseline was about 27 meters higher in female patients as compared to male patients. But then, on the other hand, male patients are more responsive to treatment with PDE5 inhibitors. This here is an analysis of the Tadalafil trial, the first trial. And you can see here that the fraction of patients achieving the primary end point, which was also six-minute walk distance, was about 25% higher in male patients as compared to female patients. So if there are, you know, differences in treatment responses, and if there are differences in disease severity, does this translate into differences in outcomes? And the answer is yes. We learned about 13 years ago now through the study by Mark Humbert that female PAH patients indeed exhibit better survival than male patients. You can see the hazard ratio for dying in the female subjects was significantly lower as compared to men. And this was the first study that showed that. This has since then been replicated in various cohorts all across the world. This here is from a Dutch population. Again, you can see higher survival in female patients as compared to male patients. And a few years ago, we looked at a large cohort of patients with all types of pulmonary hypertension in the VA CARD system. So these are veterans, mainly men, but also a few women, predominantly with group 2 and group 3 pulmonary hypertension, as you can imagine. But even in this very diverse cohort, you can see that the survival is higher in female patients as compared to male patients. And for those of you who do pulmonary hypertension, you may know that right ventricular function and right ventricular adaptation is really what drives survival in this disease. So this raises the question, are there also sex differences in RB function in PAH? And the answer is yes. Steve K. Wood showed this about 14 years ago in chest. He did cardiac MRIs on male and female PAH patients. And Steve found that the right ventricular ejection fraction, or RBEF, was indeed higher in female patients as compared to male patients, even when adjusted for things like age and body size. And that study that I showed you a few slides ago demonstrated that about 40% of the survival difference between male and female patients can be explained by a higher RBEF after treatment initiation in female patients. So this is PAH. And we recently have learned that superior RB adaptation is also observed in other types of pulmonary hypertension. Again, this is the BA CARD study that we looked at with patients with mainly group 2 and group 3 pulmonary hypertension. I showed you these survival differences. But we also found that the right atrial pressure was lower in the female patients, suggesting that maybe there's better right ventricular adaptation in this patient population. And Curt Prince published four years ago in a pure group 3 population when using right ventricular fractional area change as a readout, again, that RBEF function is higher in females, shown here in red, as compared to the males. And this held true even though the women had higher pulmonary vascular resistance, so better RB function despite higher RB afterload. And while these studies are all cool and exciting, really the gold standard for looking at right ventricular function and pulmonary hypertension is performing RB pressure volume loops with an impedance catheter. You may remember this from your medical training. You can see the pressure shown here on the y-axis. The same is shown on the x-axis. And you get these loops here over the cardiac cycle. This point here is the encystolic pressure when you ask the patient to perform a Valsalva maneuver. And you get several loops. You can look at the slope of this line connecting the various encystolic pressure points. This is called the encystolic pressure volume relationship. And when you look at the slope of this line, you get what's called encystolic elastins. And this is really the gold standard indicator of right ventricular contractility. And then when you connect the encystolic pressure with end diastolic pressure and volume and look at the slope of this line, you get what's called arterial elastins. So this is the gold standard measure of RB afterload. And then when you look at the ratio of these two, so EES over EA, you get what's called ventricular arterial coupling, or RVPA coupling. So this answers the question, for any given increase in RV afterload, does the right ventricle generate enough squeeze, enough pump function to overcome for this increase in afterload? This is exemplified here. You can see in the pink and blue, these are right ventricles with maintained coupling. So their EES over EA is around 2, as compared to this RV here with an EES over EA closer to 1. And this is what we called an uncoupled RV. So we teamed up a few years ago with Kodar Tello from University of Gießen to ask, are there gender differences in RVPA coupling in pH when we employ this gold standard method? This is the cohort that we looked at, 57 patients with pH, fairly typical pH cohort. You can see many of these patients were either on dual or triple combination therapy. And interestingly, when we looked at standard right heart catheter readouts, what you typically get in clinical practice, we did not find any sex differences between the two populations. But then when we looked at RV contractility, so again, this is encystolic elastins, you can see that the female patients indeed exhibit higher contractility as the male patients. And this was observed when we looked at the entire cohort, as well as specifically the patients with idiopathic pH. And then when we looked at RVPA coupling, so again, EES over EA, again, you can see better RVPA coupling in the female patients as compared to the male patients. And this relationship held true in the entire cohort, as well as in those patients with idiopathic pH. So this is contractile function. We also found that there's better RV diastolic function in the females. This here is the tau parameter. You can see this was lower in female patients, indicating better diastolic function. And maybe not surprisingly, this was accompanied by lower right ventricular mass in the female patients. So in summary, I've shown you that gender differences exist in pH, prevalence, disease severity, and treatment responses. Women with pH, as well as other types of pH, exhibit better RV adaptation and survival than male patients. Women with pH exhibit better RVPA coupling and RV diastolic function than their male counterparts. And a better understanding of the mechanisms underlying these sexual dimorphisms may then ultimately lead to the development of novel and gender-specific therapies for patients with pH, as well as other types of pH. And that's work that's currently going on in our lab. So with that, I would like to close and thank my lab and collaborators and funding sources, Cori Venticullo, Coder Tello, and Manuel Richter performed several of the analysis that I showed you here. And I'm happy to do questions when we're done with the last talk. Okay, thank you. I want to thank Dr. Rajagopal for inviting me to speak and the organizers as well. So I am based in San Antonio, UT Health San Antonio, as well as the South Texas VA Health System. And we're going to try to cover obstructive lung disease in women. I have no conflicts of interest as related to the topic. And we'll talk about the sex differences in some common obstructive lung diseases. So here's kind of what we always thought about for COPD, the pink puffer and blue bloater, for Netter's drawings. But really, we have to think about this as also part of the face of COPD. So we know that COPD is a third leading cause of death worldwide. In the US, in fact, the mortality in men has been decreasing, but in women, actually stable to increasing when you look over a 20-year time period. We know that tobacco smoking is the key environmental risk factor. But when we think about cases in never smokers, 30% of these cases worldwide are in never smokers. This is primarily due to biomass exposure. And the majority of these cases are in women in low and middle income countries. So way back when Marilyn was part of this, the Chess Foundation, some of the reasons that were targeted in the US with advertising towards women, and this is kind of the historical picture of that. And what we end up in currently, if you look at 2021 CDC data, in the US, 10.1% of women smoke, 13.1% of men with overall adults in the US is smoking, of 11.5%. So some differences in COPD in women versus men. In women, there's an earlier onset for the same amount of tobacco smoked. They have more exacerbations. They experience more breathlessness and dyspnea. They have worse pulmonary function, again, for the same amount of tobacco smoked. Generally lower BMIs. We talked about more biomass, less tobacco-related COPD. More comorbidities, including anxiety, depression, and osteoporosis. Overall reported worse quality of life. We know that in women, COPD is often underdiagnosed. On imaging, they have less emphysema than men. They have more small airway disease, and there are some recent data suggesting that women have a greater decrease in DLCO at baseline, as well as an increased rate of decrement in DLCO. So what are some of the possible explanations for these gender differences? Hormonal is certainly something to think about. We know that menopause and COPD can be associated with accelerated lung function decline. There can also be immune dysregulation. And one of the commonly thought of differences is due to airway size. And this was a relatively recent article in Radiology. On your left is a man about the same height as the woman on the right-hand side of the slide. And these are 3D reconstructions of the CT showing airway sizes. And you can see just pictorially there's a big difference in the airway sizes. So when you think about this, how does this make sense? So if you're smoking or have biomass exposure and you have a smaller surface area receiving the same amount of toxins potentially, perhaps that could explain some of these differences in COPD. So one of our assignments was to talk about differences in therapy. And this is a study on sex differences in adult asthma and COPD therapy, a systematic review. We'll talk first about COPD. It was designed using a PRISMA-P PICO framework format. There were 32 studies that were reviewed. And what you see here is a dot of 100 circles. And those that are in red are studies where women responded significantly better than men. In blue, men responded significantly better than women. And the gray, equal response. And the authors concluded that for COPD, there is inconsistent evidence to support differences between men and women in treatment effectiveness for COPD. Now let's shift to asthma. We know that in pre-puberty, it's more common and more severe in men. That changes around puberty, and then for the rest of adulthood, both more prevalent and more severe in women. Here again, I have one of these charts trying to indicate some of the differences. So we're talking about women have more severe asthma, more non-allergic asthma, more T2 low disease. They may have under a misdiagnosis more often compared to men, more hospitalizations, worse symptom perception, comorbidities again are increased in women, including obesity, GERD, and psychotropic med use, overall a worse quality of life described despite the severity of the asthma, and then in some studies, less likely to receive recommended pharmacotherapy. So why might some of these gender differences in asthma occur? Well, there are numerous postulated reasons. We talked about the airway size, as mentioned here again, certainly sex hormone changes can be related to social environmental exposures, effectiveness of medications, we'll talk a little bit more about. We mentioned comorbidities and then genetic and epigenetic differences. So what supports a hormonal theory? We know that there could be perimenstrual or catamenial asthma worsening. For first-time users of contraceptive pills, there's an increased incidence of asthma compared to non-users in some recent studies. There's potential improvement in asthma after menopause, and there are conflicting data looking at hormone replacement therapy, with one recent study showing that treatment with exogenous estrogen is associated with an increased incidence of asthma, and discontinuation of the HRT is associated with improvement. Back again to that systematic review I mentioned. So here you see a little bit of a different picture for asthma. Again, the red dots, women responding better than men, blue, men responding better than women, gray, equal. And here the data of those 32 pretty large studies would suggest that 44% of the evidence supports that men responded better than women to therapy. The authors further broke that down looking at different medication classes on your X-axis, I guess, and number of evidence on your Y-axis. They also looked at different parameters, such as lung function, exacerbation, symptoms and disease control. And what you could see here with a predominance of the blue is that ICS were less effective in women than men for asthma, but there was equal effectiveness for the use of combination ICS, LABA, and LAMA. And when you think back to why this might be explained, in general, there's lower allergic asthma and, I'm sorry, more non-allergic asthma and more T2 low asthma in women. So that might explain the ICS difference in terms of treatment response. I had to mention a little bit about asthma in pregnancy. Affects 2 to 13% in pregnant women worldwide, 5 to 8% in the U.S. We know that increased fetal and maternal morbidity and mortality is associated with poorly controlled asthma. This includes preterm labor, preeclampsia, placenta previa and intrauterine growth restriction. And beginning in Jena 2014, pregnancy was listed as an identifiable independent risk factor for asthma exacerbations. We teach the one-third rule, so one-third of patients with asthma, the asthma will improve during pregnancy, one-third stay about the same, and one-third may worsen. And some of the ways to possibly predict how asthma might do it in pregnancy is the severity in the non-pregnant state and if they've had a prior pregnancy, how well or poorly controlled their asthma was. It tends to worsen sometimes during the second trimester around delivery and sometimes in the postpartum period. And some of the contributing reasons for worsening could include increase in GERD due to decrease in lower esophageal sphincter tone, increased sinusitis, allergic rhinitis, and changes in compliance. So often women may not want to take their maintenance therapy if their asthma is doing well, for example, in pregnancy. In general, the asthma stepwise approach in pregnancy is the same as that in the non-pregnant patient, at least until this very last Jena iteration. So in general, you would increase your ICS. Budesonide is the only Category B agent. All the rest are C. But that being said, if you are initiating, you would use budesonide. But if you're well-controlled on a different ICS, you probably wouldn't change. Generally LAMAs are not recommended. There are not great human data and the animal experience could suggest that there is some toxicity. But one of the caveats that's recommended is that generally you do not step down asthma therapy during pregnancy. As I said, the MART and AIR, that has not yet translated to this recent addition of the Jena Guidelines. So what is stated in Jena 2023 regarding pregnancy? And these are mostly Level of Evidence A. Advantages of actively treating asthma in pregnancy outweigh any potential risk of controller and reliever meds. ICS reduces the risk of exacerbations during pregnancy. Stopping ICS during pregnancy is a risk factor for exacerbations. Exacerbations, as we mentioned, are associated with adverse maternal and infant outcomes. Unusual doses of ICS and LAMAs are safe. A Level of Evidence C, ICS should not be stopped in preparation for pregnancy or during pregnancy. And then a consensus Level of Evidence D, low priority to step down until after delivery. A word about perimenstrual catamenial asthma occurs in 20% of women and asthma tends to be worse in the premenstrual phase. They tend to be older, have more severe asthma at baseline, increased BMIs, have had asthma for a longer duration of time, and have an increased incidence of aspirin-exacerbated respiratory disease. More often, they have dysmenorrhea, premenstrual syndrome, shorter menstrual cycles, and longer menstrual bleeding. And Level of Evidence D in Jena, generally you manage this the same as in other situations of asthma, adjustment of oral contraceptive pills or LTRAs can be considered. So in the last couple minutes, let's just touch on bronchiectasis. These are from the Breathe ERS publication. In the green is CF. In the orange, non-CF bronchiectasis. So one can see that in adults for CF, of course genetically it's equal by nature of the disease. But men tend to have worse bronchiectasis in terms of prevalence, more identified. But women have more severe bronchiectasis in CF. For non-CF, I think we all think of it as the Lady Windermere Syndrome for adult patients with non-CF bronchiectasis, women generally have more prevalent and more severe disease. There are also some interesting differences when you look at infections that are part of the vicious cycle, bronchiectasis, CF here shown on your left. So men have more streptococcus and steno, women more pseudomonas. And the other thing is that it converts the mucoid variant of pseudomonas more often in women and at an earlier age. And for non-CF, men have more H. flu and pneumococcus and staph, women have more pseudomonas, again, it converts to mucoid more commonly. And we always think about NTM in women, so that's an important difference. And then finally, what are the differences in treatment outcomes for non-CF NTM? We have to think about it in women. There's a survival disadvantage in females across all age groups in non-CF bronchiectasis. There are clear gender differences in treatment outcomes, but there is this one study that suggests that perhaps macrolide therapy in non-CF bronchiectasis was associated with a greater reduction in exacerbation frequency ratio and better scores on St. George respiratory quotient. For CF, we know there's greater rate of exacerbation in females post-puberty. There's decreased survival in females, sometimes referred to as the CF gender gap, unclear gender differences in treatment response. But sometimes lower treatment adherence in females, and in younger females, generally an acceptance of being underweight also plays a role of factors here. So basically, in summary, sex and gender influence chronic obstructive lung diseases in multiple parameters. I tried to highlight some of the most important ones here. And with that, I'd like to thank you for your attention, but also wanted to point out the series of articles that Marilyn mentioned, and members of the panel, as well as in the audience, were the authors of these articles. So thank you very much. We're out of time for questions, but we'll be up here if you have any questions, feel free. I will give a plug for the Women's Luncheon, as well as our Women in Chest Medicine group. And for any of you who have interest in supporting women in medicine, practicing medicine, but also for women's health, please join. Thank you.

women

lung disease

catamenial disease

pulmonary hypertension

obstructive lung disease

endometriosis

sex differences

COPD

asthma

treatment outcomes

Chronic Obstructive Pulmonary Disease

PH