Hi all. How are you all doing? Bright and early. I guess we're also all kind of jet lagged by definition, right? So I'm Anna Nolan. I am from NYU. I do personalized medicine, so I guess that's why I'm here with you guys today, and my co-moderator. Good morning, everybody. My name's Eleanor Summerhill. I am at Leahy Medical Center outside of Boston, and I have a background in personalized medicine, but at the present time, I'm not really doing that, but asthma and COPD genetics. Great. Okay, so our third speaker thus far has not uploaded his talk. Is he here? Mr. Ahmed Ekeperi? No? Okay. So we're going to start with the first speaker today, and that is Richard Barbers from LA, and he is speaking on behalf of his resident, I believe, today. His talk is about IL-CS2S with interferon receptor 2 expression, our potential therapeutic targets for asthma. There's just a few little announcements we have to make, though, before Dr. Barbers starts. So CHESS wants to make sure that we remind everyone that you can evaluate the sessions through the mobile app or on the online program, and please don't forget to evaluate the program after it's finished. All of the presenters need to verbally disclose any possible financial relationships relevant to their presentations or just say that they don't have any, and it says that no personal recordings of the content of this meeting are allowed, although I have to say I do see people taking pictures of slides all the time, and I think that that's really it. So welcome, Dr. Barber. Thank you so much, and also thank you for the invitation. I am not really the real presenter. I am presenting for Pedram Shafil, who actually did the work for the past few years, and Pedram is in his second year of medical school, and this is exam week for him, so I gladly pinch-hit for him. So this is really an acknowledgment to his work. I participate a little bit, but not to the extent that he did. So the title of his talk is Novel Approaches to Understand and Treat Allergic Disease and Asthma. The objectives here is to discover the link between ILC2, the new population of cells, TNF-alpha, and allergic asthma. The question is how the TH2 paradigm is changing in allergic asthma, and can TNF-alpha affect ILC2 function and airway inflammation, and could targeting the TNF-alpha, TNFR receptor, that is, be a therapeutic strategy in ILC2-dependent asthma. Some background in terms of the genetic and environmental influences in asthma. We know that there are persons with genetic predisposition to asthma, and there are inducers, like allergen. You get an inappropriate immune response, that's the TH2 response, that leads to airway inflammation and recruitment of a variety of cells. Then there are triggers that cause bronchoconstriction, stimuli like allergens and irritants, and you get the clinical picture of the signs and symptoms of asthma with wheezing, cough, and chest tightness. This is a cartoon diagram of the complexity of what we know and have learned about the asthma pathogenesis in terms of immunopathogenesis, and you can see the variety of cells involved, nodes, in fact, also the epithelial layer. Yet not all phenotypes would fit the TH2 paradigm. Interferon gamma, IL-17, TNF-alpha, and neutrophils are frequently found in the lungs. Many pulmonary chronic infections, particularly with viruses, cause asthma. Obesity, exercise, and air pollution-induced asthma are often non-TH2 asthma. Most patients who are sensitized to allergens do not develop asthma, and TH2-targeted treatments have not been as effective, as hoped, in many clinical studies of asthma, and many patients remain unresponsive to current therapeutic options. So what are the factors or components that are absent or inadequately accounted for? Well, the discovery of innate lymphoid cells may be an explanation. We have RAG2 model, and RAG is a recombinant protein involved in the generation of T and B cell receptors, which give survival signal to the adapted immune cells. They're exposed to IL-33, and then the lungs and bowel, bronchoalveolar lobotomy, are collected, and you see an increase, or at least a profile, of IL-5, IL-13, airway hyperactivity, and eosinophils. In the knockout RAG2 models, also exposed to IL-33, the lung cell samples, the bowel, are looked at, and you do find some of this, but not to the extent that you find the IL-5, IL-13, airway reactivity, and eosinophils in the non-knockout models. Yet, these cells are IL-33 responsive. They're TH2 cytokine producing, and non-T and non-B cells do exist. So, looking at our cartoon, where does this fit in? Where does IL-C2 fit in? And, as you can see in the diagram here, yes, it does have a role in this immunopathogenesis, and as I said, it's a fairly complex immunopathogenic model. So, what about IL-C2s and asthma? As I said, they have a role in asthma persistence, they maintain airway hyperactivity, and airway remodeling in the absence of T-cells, and this has been shown in other studies. They also have a role in asthma exacerbation, and they prompt response to respiratory viral infection and allergens. So, you can see here where IL-C2 cells also have a profile that's similar to the TH2 cells, and the question is whether or not they are in that TH2 or T2 model. So, what are the most effective methodologies and approaches for identifying and investigating the biological mechanisms and characteristics of IL-C2? This is how IL-C2s have been isolated. They have various markers in terms of their lineage, as you can see here, and in the naive lungs, IL-C2s represent only one to two percent of total lymphocytes. So, even though they are a small part of the immunological milieu, they are a very dynamic population in the lungs. Over the past 15 years, there has been a significant surge in interest in the biology of type 2 innate lymphoid cells, that's the IL-C2s, and their therapeutic potential. This is a fairly complex diagram, but just to show you that IL-C2s are rapidly activated, and in particular, the alarm is, as you can see at the top of the diagram, but have a complex and dynamic regulation in terms of activation, in terms of the, that's hard to see, but other than that, but as well as inhibition and trafficking, and in particular, our lab was interested in the TNF-alpha markers. So, tumor necrosis factor alpha, it's involved in proliferation, in cell survival, and differentiation, and one of the authors, and who is in the lab, looked at signaling, which enhance, again, as I mentioned, proliferation, function, cell survival, differentiation, and the induction of airway hyperactivity. So, let's look at a clinical model. There were healthy donors, as well as asthmatics, in three different categories. Peripheral blood was obtained, a FACS analysis was done, and you can see here the demographics of the patient population, and looked at IL-C2 components in all of these separate groups. We also looked at TNF receptor 2, and also you can see that they are expressed in these various groups. Now, obviously, we haven't done enough experiments in order to find out which group had the most expression. So, how is TNF receptor 2 expression induced on IL-C2s during lung inflammation? And we found that if we look at IL-33, one of the alarmins, they do induce TNF-R2 expression on these cells, and you can see here the intensity of the fluorescence with IL-33 in controls, as well as those who have TNF-R receptor 2. Now, can the engagement of TNF receptor 2 on IL-C2s modulate their effector function? Again, looking at a model of healthy donors, as well as those, well, in particular, these are healthy donors, and expose them to 33-TNF-alpha, as well as TNF-R receptor 2 inhibition. And you can see here, again, their expression for IL-5 and IL-13. So, they still produce, yet perhaps if the IL-32-TNF-alpha may have the most expression of 13-N5. So, in summary, human IL-C2 are drivers of type 2 inflammation of the allergic asthmatic. The number of circulating IL-C2s increase in asthmatics. IL-C2 isolated from severe asthmatics selectively have increased TNF receptor 2. TNF receptor 2 expression is inducible on human IL-C2s by IL-33. Blocking TNF receptor 2 and IL-C2s decrease IL-5 and IL-13 production. So, where are we going? Well, we continue to recruit healthy donors and patients with asthma, explore the application of the immune cell checkpoints, and profile human samples to, for biomarkers for these subtypes. Thank you so much. And just an acknowledgement to the people in the lab with Dr. Akbari and our sponsors and person, sorry, those who funded us, and also the clinical team at USC. Thank you. So, the next speaker will be Dr. Zainab Gandhi. Welcome. So, her talk today will be a national analysis to assess the effect of lung volume reduction surgery in COPD patients with concomitant pulmonary hypertension. Thank you. It takes a bit to load. Yes. All right. Good morning, everyone. My name is Zainab Gandhi. I'm a third-year internal medicine resident at Geisinger, and my topic today is a national analysis to assess effect of lung volume reduction surgery in COPD patients with concomitant pulmonary hypertension, and I do not have any relevant disclosures. These are the authors that have worked on this project, so just a shout out for them. So, our hypothesis was that lung volume reduction surgery in severe COPD patient provides symptomatic benefit to selected patients. It improves quality of life and may be considered as a bridge to lung transplant. However, WHO Group 3 pulmonary hypertension is well associated with COPD, so we aim to evaluate if lung volume reduction surgery influence outcomes in patients with COPD with associated pulmonary hypertension. So, a little bit of background why we were interested. So, some of the very early literature in this topic is a Blue Journal article in 1999 where they took patients who had COPD with associated pH, and they found some worsening of pulmonary hemodynamics with mean and systolic pressure, and since then, COPD with concomitant pulmonary hypertension has been a contraindication for lung volume reduction surgery, and here on the right is just a table, and even today, having associated pulmonary hypertension with severe COPD remains exclusion criteria, but since that paper, there has been a lot of studies that, or at least I'm going to talk about four to my knowledge that have reevaluated this. So, on the upper left is a study that was done by Eberhard, and they took a very small group of six patients who had severe emphysema with established pulmonary hypertension who underwent endoscopic lung volume reduction with endobronchial valves. Now, these patients, they had, they followed them for 90 days after the surgery, and they found improvement in their mean pulmonary artery pressure. They also found improvement in systolic pressure, six-minute walk test, and cardiac index, and then the study on the lower right studied the impact of the similar procedure, but how it impacted the right ventricular myocardial function, and this study was done in a total of 32 patients, divided in two groups of clinical responders and non-responders, and they found both groups had improvement in right ventricular longitudinal strain, again, 90 days follow-up. However, they did not see an improvement, a change in global strain, but it was promising to note that there was reversibility of RV function as well. So, how is this also affecting hemodynamics? Again, two studies that I think are landmark for this field would be the NET trial on the left, again, published in the Blue Journal in 2007. It was done primarily for lung volume reduction surgery and outcomes, but they also assessed the cardiovascular parameters, where they found patients with lung volume reduction surgery group compared to the medical group had lower systolic pressure, diastolic pressure in the pulmonary arteries, pulmonary artery mean pressure, and wedge pressure, and then the most recent study, again, who re-evaluated this, they took, on the right is the diagram from that patient group, and it's a European study. They took about 30 patients, and they divided these patients based on the pulmonary artery pressure, and the patients with more than 35 were a pH group, and then the other group was less than 35, which was the non-pH group, and as you can see, the pre-op pulmonary artery pressure as opposed to post-op pulmonary artery pressure has significant improvement, again, 90-day follow-up, but this study was interesting because they also followed these patients for survival, and none of these patients, they all survived, I guess, they didn't die, so there was, this was exciting because there may be a mortality benefit to it as well. So there may be no harmful effects to pulmonary hemodynamics with lung volume reduction surgery status, and there may be an overall mortality benefit to lung volume reduction surgery in severe COPD patients with associated pulmonary hypertension. So with this hypothesis, we took the dataset that's National Inpatient Sample Database, it's hospitalizations across United States, and we took the timeline from 2016 to 2020. Our population was COPD admissions using ICD-9 and 10 diagnosis code. We compared patients with lung volume reduction status with versus without pulmonary hypertension, again, using relevant ICD-9 and 10 codes. Our outcome of interest was primary outcome being baseline demographics and comorbidities and all-cause mortality, and secondary outcomes were length of stay and healthcare utilization. So in terms of baseline demographics, we found that the patients with the group of pulmonary hypertension were older. Both groups were less likely to be female, but it was not statistically significant. Both groups were predominantly Caucasian, however, again, it was not statistically significant. That's why I've highlighted it in another color. The CCI index of two was much higher in the PH group as compared to patients without pulmonary hypertension. Both groups were predominantly Medicare insurance type and admitted to the large hospital bed size. In terms of comorbidities, again, the ones that are highlighted were not statistically significant, so I'll just mention that at the end, but patients with pulmonary hypertension were much more likely to have congestive heart failure, cerebrovascular disease, rheumatoid disorders, peptic ulcer disease, diabetes with complications, CKD, hypertension, and anemia. They were less likely to have benign tumor and metastatic tumor. Again, the comorbidities that were not statistically significant were acute myocardial infarction, peripheral vascular disease, dementia, mild liver disease, and diabetes without complication. So these were our outcomes. In terms of the inpatient mortality, we found the odds ratio was 0.93, however, it was not statistically significant. In terms of our secondary outcomes, we found that patients with pulmonary hypertension had a much longer length of stay as compared to eight days versus 20 days, and the total cost was almost three times for patients with pulmonary hypertension. I just wanted to highlight limitations. We've done several analyses on national inpatient sample, and this has come up in time, so NIS is dependent on billing and coding, so lack of diagnosis at a clinician level or coding error remains inherent to the collection of administrative data and to the database, and residual confounders due to retrospective analysis. This data is also encounter level instead of patient level data, and we were unable to classify and quantify the severity along with more than one WHO group of pulmonary hypertension in the COPD patients, so if there is a correlation to outcomes. And while we were unable to demonstrate mortality benefit, further studies are warranted to assess change in quality of life metrics such as exercise capacity, change in lung function, and echocardiographic measures which could affect outcomes for our patients. So my conclusion would be that COPD hospitalizations with associated pulmonary hypertension who underwent lung volume reduction surgery did not find any statistically significant difference in mortality outcomes. They had increased utilization of healthcare resources with length of stay and healthcare costs. COPD hospitalizations with associated pulmonary hypertension who underwent lung volume reduction had three times higher CHF, two times higher rheumatoid disorders, however lower benign and metastatic tumors, which could mean that there could be concurrent presence of another WHO group pulmonary hypertension which could be a confounder to mortality outcomes. And thank you. I can take any questions. Okay, so we move on to our fourth talk of the day. I still have not seen the third talk uploaded. So this will be Dr. Hoyt. Her talk today will be on factors associated with reduced asthma severity and improved asthma control in the Severe Asthma Research Program III. Hello, so today I'll be talking about factors associated with reduced asthma severity and improved asthma control in the Severe Asthma Research Program III. My name is Olivia Hoyt, and I'm a clinical research coordinator at the Asthma Research Center at Brigham and Women's in Boston, and I have nothing to disclose. So our objective is to look at factors such as patient characteristics, comorbidities, and environmental factors that may be associated with changes in asthma severity over time or changes in asthma control over time. Therapies are aimed at treating symptoms and airflow obstruction. Asthma management does involve the continuous cycle of assessing patients, adjusting treatment, and reviewing responses. And about 5 to 10 percent of the asthma population does have severe asthma, though this number is not, this population isn't static, as severity can change over time with treatment of asthma and comorbidities as well as the avoidance of triggers. Asthma control can also vary over time as symptoms fluctuate. And so like I said, we'll be looking at patient characteristics, comorbid conditions, and environmental factors that are associated with improved versus persistently severe asthma over time as well as improved control versus persistently uncontrolled severe asthma over time. And we looked at the Severe Asthma Research Program study. This was a six-year longitudinal observation study in seven sites across the United States. There was also a very diverse sample of subjects in this study. At least 50 percent were female and at least 30 percent were non-white. And patients in this study did have good adherence to their asthma treatment as those with evidence of poor adherence were excluded. Severe asthma in the study was a Severe asthma in the study was defined as high-dose inhaled corticosteroid use with a second controller in addition to daily systemic corticosteroid use or uncontrolled asthma or a deterioration of their asthma when their medication was removed. In our analysis, we included severe asthma participants who had at least one follow-up visit in the study, and their severity was assessed at both their first and last visit in the study. For uncontrolled asthma, we defined that as an asthma control test of less than 20, and an improvement in asthma control was defined as an asthma control test greater than or equal to 20 with at least an increase of three points from their baseline. We compared factors between participants with reduced asthma severity versus their persistently severe asthma participants, and we also compared factors between improved severe asthma control versus participants with persistently uncontrolled asthma. And we used chi-squared tests, Mann-Whitney u-tests, and two-sample t-tests for this comparison as well as using logistic regression for the multivariate analysis. The average follow-up time for participants for the baseline severe participants in the study was 5.4 years, and of the 525 adults in the study, 321 of them were classified as having severe asthma at baseline. At the end of the study, 87 of those participants were reclassified as having non-severe asthma, about 27 percent. For control, we did look at those participants who did have severe asthma and uncontrolled asthma at baseline, which was 239 of the participants, and at their final visit, 64 participants were reclassified as having controlled asthma, again about 27 percent. So as you can see here, those with a decreased severity of their asthma were more likely, or there was a higher percentage of females in that group, and this group also had a higher baseline lung function testing. In these baseline characteristics, those with decreased severity also had lower incidences of vocal cord dysfunction, nasal polyps, and environmental allergen sensitization, as well as fewer symptoms of insomnia. In the multivariate analysis, it showed that the participants who had decreased severity did have a higher lung function testing at baseline, and they were about half as likely to have environmental allergen sensitization, about eight times less likely to have vocal cord dysfunction, and were slightly less likely to have insomnia symptoms. And the baseline characteristics for those who had improved control versus persistently uncontrolled asthma, those with improved control at baseline did have lower BMI, lower waist circumference, higher lung function testing, as well as increased exhaled nitric oxide, and a much lower rate of current daily smoke exposure. Again, these participants with improved control also had lower rate symptoms of depression, as well as a higher asthma control test at baseline, and fewer symptoms according to the ACQ-6 form, as well as higher scores on the asthma quality of life questionnaire. In the multivariate analysis, it did show that those with improved control did have higher lung function, about 20% more likely to have a higher lung function, and they did have a higher eosinophil count as well, and an increased asthma control test, and asthma quality of life questionnaire. These participants who did improve in control were about half as likely to have had an exacerbation in the past year, and were only about a fourth as likely to be exposed to current daily smoke exposure. They did have fewer symptoms of depression, and fewer asthma symptoms according to the asthma control test, as well as lower waist circumference. So, in summary, subjects with severe asthma who were reclassified as having non-severe asthma had higher baseline lung function. They were less likely to have baseline environmental allergen sensitization, or vocal cord dysfunction, and fewer reported insomnia symptoms. And participants who had severe uncontrolled asthma, who were reclassified as having controlled asthma, had lower waist circumference and higher lung function testing at baseline, and they were also less likely to have daily smoke exposure at baseline, or an exacerbation in the year before they entered the study. They also had a higher baseline eosinophil count, and fewer reported asthma symptoms, and fewer depressive symptoms at baseline. So, in conclusion, interventions geared towards certain potentially modifiable risk factors, such as depression, obesity, and daily smoke exposure, may deserve additional investigation to see whether they can improve asthma control. And there was also little overlap between the factors associated with improved asthma severity and improved control, which may indicate different mechanisms leading to improvement by these metrics. It's not quite on here, but you may have noticed there was a higher eosinophil count and higher exhaled nitric oxide values for participants who did have improved control, and we believe that may have contributed to their improved control, as those are more treatable factors. And I would just like to acknowledge my center and the SARP investigators as well. Thank you.

asthma

therapeutic targets

lung volume reduction surgery

COPD patients

mortality outcomes

reduced asthma severity

improved asthma control