Thank you very much, we were having some early morning jitters. So the bottom line is that every disease, asthma or otherwise, you cannot understand a disease without looking at its origin and how it evolved. And everything starts from children. So as we know, about 80% of asthmatics, the asthma start in their childhood. And if we treat them good, they do better. If we don't treat them good, they develop obstructive-restrictive lung disease, fixed airflow obstruction, very much increased risk of developing COPD as they grow older and very hard to treat in their adult life. So every uncontrolled asthma, other than non-compliant ones, is of course our fault. So sorry for that. Having said that, I have no financial relationship to disclose, and no copyright infringement is intended if I've stolen or borrowed any slides. So the objective of this talk is to determine who is at risk for asthma, because in pediatrics about one-third of the kids do these here and there, especially when they're exposed to viruses, but not all of them develop asthma. And a little update on the management of asthma in children, because it is still evolving and there's a lot of controversy between the two guidelines. And at times, we have controversies with both of them. So in brief, we have about 25 million Americans with asthma, and about 250 worldwide. Out of them, about 50% are intermittent, and another 20% are mild asthmatics. One in 10 children do have asthma. About $80 billion healthcare cost every year, about 3,000 deaths in the United States alone, and worldwide it is about tenfold. About 14 million school days missed, about 14 million workdays missed, three in five still have physical activity issues, and about two-third still don't know how to use an inhaler. And honestly, about half of the healthcare professionals don't know how to use an inhaler, and about one in five still cannot afford their medications, in spite of all the best healthcare system we have in the world. So having said that, if you want to know the relative risk of asthma, we have to look at some of the epidemiological studies, which I've done over time. I just want to mention one which is not new, but it is going on for the last about 25 years. This is what we call Tucson study. It of course started in Tucson. They took about 800 children who were born in that year, and followed them over 22 years. They noticed that about 50% of them never wheezed, so they were not at a risk of asthma, whereas about one-third, about 20%, had some wheezing during the first year of life, and they wheezed for two, three years, and then by three years of age, they stopped wheezing, and they never wheezed again, and they did not develop asthma. Those were the kids who were born to mothers who smoke, had small lungs, and as with time the lungs matured, their physical limitation was resolved. Then another about 14% were the persistent wheezers, who started wheezing when they were very young, by one or two years of age, and continued to wheeze when they were up to six years of life, and some continued even after that. Those were mostly those who were exposed to viruses and had viral bronchiolitis, and thus continued to wheeze, but even then, not all of them developed asthma. About half of them were non-atopic, and they quit wheezing by the time they were five, six years old, and never developed asthma, whereas there was a fourth group, another about 15%, who were the late wheezers, who started wheezing when they were around five, six years of age, and continued to wheeze. Those were the kids who had early sensitization to the environmental allergens, and many of them eventually developed asthma. So about 70% of the adult asthmatics were from the third and fourth group. So if you look at the number of other studies, which will clearly tell you that about 20% of the asthmatics start developing asthma symptoms when they are less than one year old, another 20 by two years, another 20 by three years. So practically 70% of the asthmatics, which we have as an adult with asthma, do start their symptoms very early in life. So if they are not picked up early and treated early, they can have irreversible limitations of their lung functions, and more severe form of asthma, and as all of you have seen the Melbourne study, which have clearly showed that those who have uncontrolled asthma, by the time they are five, six years or eight years of age, their lung functions are significant, about 10 to 15% lower than the normal kids, and after that, no matter which medication you give to them, after in their 45 years follow-up, their lung functions do not improve. So you have to pick them early and treat them early. And another reason for picking them early is that we all know that in pediatric asthma at least, most of the morbidity is associated within the first five years of life, and after that, from five to 10 years, it decreased by one-third, and then from 11 to 17, it decreased by another one-third, and that is usually the adult morbidity. So the pediatric morbidity table is very different than the adult morbidity, so first four years are very important. But then again, remember, about one-third of the children or about 50% of the children do have off and on wheezing during the first three, four years, so you can't put half of the population on an inhaled medication. Pharmaceutical companies will love that, but I don't think that will be a cost-effective way to treat asthma. Another two good landmark studies, one in pediatrics, one in adult, which have clearly shown a similar pattern that the more is the delay in starting inhaled steroids in anyone who have asthma symptoms, the less is the recovery of the lung functions with time. So those who are having symptoms for more than three, five years, and in them, even after starting the adequate therapy, the FEV1 or the peak flow do not come back to normal, so early treatment is essential. So that leads to the next step, how to figure out that out of the one-third of the population who's wheezing, which one will gonna develop asthma? So this is Rodriguez Asthma Predictivity Index, which was proposed many years ago, and it still stands, and it is a broad, more clinical pattern, but what it says is that if in last one year, you have three or more episodes of asthma, or at least one of them are physician diagnosed, it's not all mom's perception, and then if you have one major criteria or two minor criteria, your risk of developing asthma by six years is about 65%. If you have none of those, your risk of not developing asthma is 95%, so it's a very good negative predictive value, but if there are any of these criteria present, those are the kids you target with the therapy early on, so if their mother or father have asthma, if they have eczema, or if they become early sensitized to the environmental allergens like ragweed, cats, dogs, grasses, trees, grandma, and you can pick whichever you like. And then two minor criteria, wheezing without a viral infection, increased eosinophilia, and allergic sensitization to the food allergen. So this was the first time food allergies were included as a risk factor for developing asthma. Now, at the end, I'd just briefly like to mention the controversies in pediatric management of asthma in current guidelines. The most important thing in these guidelines is that if your patient is doing fine, please leave him or her alone, because that is the most important and most difficult thing for us to do. Now, with current GINA guidelines, they have combined both mild intermittent and mild-precedented asthma as one, and call it a mild asthma. And their recommendation is that we should not use as needed albuterol. Instead, if younger kids use inhaled steroids whenever the short-acting beta-2 agonist is needed, and in older children and adults, use inhaled steroids, plus formaldehyde, whenever they need, they have any wheezing or respiratory symptoms, and if it doesn't work, then go to a smart therapy, which means that all of the asthmatics, irrespective of their severity, need to be on as-needed inhaled steroids or anti-inflammatory medications, even if they have intermittent asthma. And the theory behind this, that even with the intermittent asthma, they can have severe flare-ups, they can be hospitalized, so it's better to treat them with inhaled steroids instead of just the short-acting beta agonist. And this is the guidelines, 6 to 11. They start with low-dose inhaled steroids, plus Seba whenever someone is sick, and this is 6 to 11, and above 11, the first step is as-needed inhaled steroids, and formateral. So there is no room for intermittent asthma. Everyone needs to be on either inhaled steroids or a combination medication. So it might work for adults, but I'd just like to quickly mention a very interesting study which came three, four months ago. It was from Texas Children's Hospital, and it was done by Hal and his group, and their aim was to determine the risk of asthma hospitalization and emergency room visits for pediatric members of the Texas Children's Healthcare Plan, who had a diagnosis of asthma, and who was prescribed less than two short-acting beta agonist canisters per year, which by definition was intermittent asthmatics. There were about 45,000 children in that group. They also looked at, included those who had no hospital admission or emergency room visits and no prescription for inhaled or oral steroids in the last one year. So their criteria was even more stringent than the intermittent asthma criteria. And then they followed those patients for one year, and then they looked for the hospitalization and emergency room visit in that group. They saw that the patients who had no inhalers of albuterol prescribed in one year, their follow-up and follow-up risk, their risk for hospitalization was 1.1 per 1,000, whereas those who had required one to two inhalers, their risk of hospitalization was 1.5 per 1,000, which were both were not statistically different, and they, in average, they had 1.4 per 1,000 hospitalization, emergency room visit was about 1.6%. One other thing which they noticed was that the kids who were less than six years old had about three times more hospital admissions compared to those who were above six years old, which was 0.7 and 2.2 per 1,000, which was statistically different, about one-third of the other. Now, they used the risk assessment analysis of NAPP guidelines, which was, I think, 0.77, to this cohort, and even in kids who were less than four years old with the highest risk of hospitalization, that analysis showed that you need about 2,900 children treated with the inhaled steroids to prevent one hospitalization. If you have the average cost of inhaled steroids in the U.S., it's about $250, which means that even if they need only one inhaler of inhaled steroids in a year, it would cost about $700,000 to prevent one hospitalization in that group. The older children hospitalization was three times less, but even if you use the same increased hospitalization data to that age group, that will be three, four times more. Now, just put that in prospect to the inhaled steroids for metarol combination, which cost about $500 per inhaler. So in that case, it would be about $1.5 million spent to avoid one hospital admission. Now, in this way, they were able to define a group which was using less than two canisters of albuterol per year without having inhaled steroids or oral steroids and no previous hospitalization, and that group was not cost-effective to start the guideline-based therapy. And their calculation was that this group may not be benefited by as-needed inhaled steroids or even a combination therapy on as-needed basis. So just keep your eyes open. It's not a blanket therapy, and it's not a small change, because there are about 13 million intermittent asthmatics in the United States and another 8 million mild asthmatics, mild persistent asthmatics, so 20 million people, therapy worldwide, about 200 million people. So apply this cost-effectiveness on 200 million, and you will have a little bit idea how much it takes to prevent a hospital admission. And thank you very much for your time, and if any questions, we can discuss it at the end. Thank you. Thank you very much, Dr. Sheikh. Okay, good morning again. I'm Navita Ramesh, Pulmonary Critical Care. I'm the Critical Care Fellowship Program Director at UPMC Harrisburg. So my talk today is going to be on stable asthma in pregnancy. So we are not going to be talking about asthma exacerbation or treating asthma exacerbation. So this is stable asthma in pregnancy. I do not have any disclosures pertaining to this talk. So in the next about 10 to 15 minutes, we'll go over all these topics listed here. So why is asthma in pregnancy important? Why should we know about this? What are the physiological changes in pregnancy that could mimic asthma symptomatology? The pediatric and the maternal outcomes of controlled versus uncontrolled asthma? How do you manage asthma in pregnancy? And I have one line about COVID and then managing acute asthma exacerbation in pregnancy. Like I said, I will mention it, but it's not the focus of this talk. So in the United States, about 5 to 8 percent of pregnant women have asthma and the prevalence is increasing every year. Worldwide, asthma affects about 2 to 13 percent of all pregnancies. Asthma exacerbations are very common in pregnancy, especially in the second trimester. And asthma is actually the most common respiratory condition of pregnancy with increasing healthcare utilization and cost. So switching gears now to the physiological changes during pregnancy, right? So we do have cardiovascular and respiratory changes that happen during pregnancy. So during pregnancy, the heart rate increases, the stroke volume increases, so the cardiac output increases. The systemic vascular resistance due to the effect of the hormones, it decreases, so there's vasodilatation. The blood pressure also decreases. That's important to understand the cardiovascular physiology of asthma. When you come to the respiratory physiology, respiratory rate may increase, tidal volume increases, and hence the minute ventilation increases. So it's important to understand that the minute ventilation increases due to an increase in the tidal volume. So moving on to more in-depth respiratory changes during pregnancy, as we know this, with increasing abdominal girth, the diaphragm is elevated due to the effect of the enlarging uterus. And during pregnancy, it could go as high as four centimeters above the usual resting position of the diaphragm. So since the diaphragm is pushed up, there's a decrease in the FRC, or the functional residual capacity in the lungs. The expiratory reserve volume is decreased, and the residual volume is also decreased. However, the FEV1 is stable during pregnancy, and there is only minor changes in FVC. So overall, the FEV1-FVC ratio remains stable, or it's the same throughout pregnancy. Okay, so the point is, if you were to do a spirometry, can you rely on your FEV1-FVC ratio in pregnant women? Yes, you can. So with that background, now moving on to the oxygen delivery to the fetus. So why do we care about keeping asthma stable during pregnancy? Not only for the mother, we need to focus on the fetus as well. So the uterine artery blood flow is near maximal at baseline. Okay, so throughout pregnancy, the uterine artery has maximal blood flow, and the maternal oxygen content in that blood is very important. We have to maintain adequate maternal cardiac output and maximize the maternal oxygen saturation. So you don't want the mother to be hypoxic, hypoxemic. In turn, the uterine blood will not have enough oxygen, and in turn, it affects the fetus. So that's with the uterine blood flow. And another important aspect is upper airway and immunological changes. So briefly, due to the estrogen hormonal changes during pregnancy, there is mucosal and laryngeal edema, which is a normal physiological pregnancy condition. This can lead to rhinosinusitis in about 20% of pregnant women. And we all know that with asthma, rhinosinusitis is one of the major comorbidities that needs to be treated in order to get adequate asthma control. This is also important to understand. If you are in the ICU and there is a pregnant patient with respiratory distress, when you're planning your intubation, I always consider it a difficult airway right from the get-go, understanding that they may have this laryngeal edema to begin with. The immunological changes is, during pregnancy, there is a shift from Th1 cytokine production to Th2 cytokine production, which is essential for the fetus to survive. This Th2 upregulation leads to asthma exacerbation for the mother during pregnancy. So the Th2 is important for the fetus, but may not be as beneficial to the mother. So we may have heard of this rule of thirds in asthma. So during pregnancy, a third of the pregnant asthmatics could get worse. During pregnancy, a third, their symptoms could get better. And in a third of them, the symptoms could remain the same. So we don't really know which bucket the patient will fall into. So if asthma is left uncontrolled during pregnancy, what are the maternal outcomes? Increased risk of preeclampsia, placental abruption, placenta previa, there's higher risk of obstetric hemorrhage, increased c-section rates, increased spontaneous abortion, and the mother could have gestational diabetes or pulmonary embolism as well. So this is based on a meta-analysis of all publications between 1975 to 2012. So they've looked at all those studies looking at asthma during pregnancy. And this is from the same study looking at pediatric outcomes if the mothers had asthma. So uncontrolled asthma could lead to low birth weight, small for gestational age infants, increased prevalence of minor congenital malformations, and the children in turn can develop asthma during their lifetime. This study is from 2013. So looking again, this is a meta-analysis looking at maternal asthma and the neonatal outcomes. And one of the conclusions was maternal asthma is associated with increased neonatal hospitalization. So with that background, so we saw the physiological changes that happened during pregnancy in patients with asthma. We went over what are the adverse maternal and fetal outcomes if the asthma is not controlled. So keeping that in mind, we'll go over management of asthma during pregnancy. So our goals is to prevent chronic daytime symptoms and nighttime symptoms in the mother, maintain optimal pulmonary function tests, and normal activities. Activity, as you know, is very important. You don't want them to be bedridden. So you want to enhance mobility, get the asthma under control so they can do their day-to-day activities, prevent exacerbations, and maintain fetal oxygenation by preventing episodes of maternal hypoxemia. So I like to call this the asthma management pie, right? So the management is divided into these topics here, five main criteria, and each one of them is important. It's not just you give the medications for asthma, for inhalers, and you expect the mother to have well-controlled symptoms. So each of those are important and we'll go over them one by one. So the first one, the first slice of pie, is monthly assessment of asthma. So it's very important to assess the mother monthly, especially in the later half of their pregnancy. Using structured asthma history and validated questionnaires, such as the ACQ, the ACT, or GINA-recommended questionnaires. Monitoring of lung function by spirometry or peak expiratory flow, and also fetal monitoring, close fetal monitoring, should begin after 32 weeks. So now you may ask, is ACT questionnaire, is it validated in pregnancy? So this is a study that was done in Brazil using the Spanish version of the ACT, or asthma control test questionnaire. It was an in-person interview of 40 pregnant women and the conclusions of the study was the ACT score discriminated between control and uncontrolled asthma and was responsive to symptom improvements during pregnancy. So if you treated the mother, the ACT score improved and this was quite well validated in these 40 patients. So you can continue using your ACT score. Now this was important especially when I was doing the literature review, especially during the COVID era, I thought this was important. So they validated the same asthma control test questionnaire in a telephone study. So the mothers did not have to go in every month just to get the asthma, the ACT test done, the ACT questionnaire. Instead this was done over the phone. This is called the mother to baby pregnancy studies. They had this between 2011 to 2013. So even before telemedicine became a thing with COVID, they did this several years ago and they found that doing the ACT test over the telephone had good internal consistency, was reliable and valid in assessing asthma control throughout pregnancy. So yes, ACT is, you can continue to use ACT, okay, as a screening test. Now when you look at the assessment of asthma during pregnancy, spirometry is still okay. You can still rely on your FEV1 over FEC ratio, as I mentioned. Peak expiratory flow can still be used. However, methacholine challenge test is contraindicated during pregnancy. And one of the other newer things we use nowadays is the FENO. So was FENO validated for asthma in pregnancy? That's the next question. So this study is again double-blind randomized controlled trial, looking at specifically using FENO in pregnant women. So about 220 pregnant non-smoking women with asthma. They were divided into two groups. They titrated the inhaled corticosteroid dose based on the FENO levels. And the second group, the inhaled corticosteroid dose was based on symptoms without looking at FENO. The primary outcome was looking at asthma exacerbations. So the conclusion of the study, as you can see in this box on the side, this one here, the FENO group had less exacerbations. The FENO group had better quality of life for the mother. And when you look at the neonate, the neonatal hospitalization were also decreased if the mother's inhaled corticosteroid dosing was titrated based on FENO levels during pregnancy. And the number needed to treat using this FENO was six. So it was not a huge number. It's very doable to do FENO during pregnancy. And it helps both the mother and the baby. This study takes it a little bit further, looking at the FENO based algorithms or management of asthma during pregnancy. And they said if the mother's inhaled corticosteroid dosage was titrated based on FENO, there was less infant bronchiolitis and less infant asthma or less childhood asthma for the child. So you can use FENO. It's very good. The next one I want to go over is telehealth. This study here, which is called the mastery study, they looked at management of asthma with support of telehealth and respiratory function in pregnancy. In telemedicine study, improved quality of life in pregnant women who use a handheld respiratory device and they use an Android smartphone to conduct telehealth visits. So that there are different ways for remote monitoring of these pregnant women. So from there, after you monitor the mother closely with using different questionnaires, different methodologies, we move on to the patient education. So preconception education is very important. As we know, at least in my experience, the expectant mothers tend to listen to their obstetrician more than they would listen to the pulmonologist. So it's good to have a great relationship with their OB. Go over the inhaler technique like in any other patient, written asthma action plan, and also address the teratogenic concerns and the risk of medication discontinuation. So as a pulmonologist, again, if you are going to tell them continue using the inhalers, they may not trust you. They may not listen to you. But the same thing coming from their OB, they may be a little bit more responsive to that. So medication discontinuation in pregnancy. So pregnant women use less albuterol. This study was done in 2003. So basically they did not use the inhaled corticosteroid, the latest GINA guidelines, right? So this was 2003. Pregnant women, they thought that the inhalers caused more teratogenic risk, and so they did not use the inhalers regularly. They were changing and prescribing habits, changes in asthma disease severity throughout the pregnancy because they weren't using the inhalers. These women who did not use the inhalers experienced increased days of wheezing. So wheezing, bronchoconstriction, eventual hypoxemia, decreased uterine, blood oxygen, not good for the fetus. Again, the last point is important. Pregnant women were likely to continue their inhaled corticosteroid medication if advised to do so by their obstetrician. So following that, the next piece of the pie is the triggers. Just like a non-pregnant asthmatic patient, we have to go over the triggers and talk about avoidance. I have listed some of the triggers there. They are similar to the non-pregnant women, so trigger avoidance is key. Comorbidities, just like you would do it and address the comorbidities in a non-pregnant patient, you would have to go over all the comorbidities and make sure all these are addressed, which include rhinitis, gastroesophageal reflux disease, which is more prevalent in pregnant women. Depression, allergies, all need to be addressed. So as you see, the pharmacological therapy is only one piece of the pie, which includes inhaled corticosteroid, short-acting and long- acting beta agonists, judicial use of oral corticosteroids. Again, it's risk versus benefit, right? Do you take hypoxemia or do you take systemic steroids? So you have to weigh risk versus benefit for the mother. And I have this last point here, appropriate continuation of adjunct therapies. More and more studies are coming out. They've looked at omalizumab in pregnant women. That's, I think, the largest biologic in pregnancy study, where they said you do not initiate omalizumab during pregnancy, but if they were on it before, you can continue it. Recent smaller studies have come out using anti-IL-5 and dupilumab. They show similar results. They are smaller studies, but they show similar results. If the mother was using it before pregnancy for better asthma control, it's okay to continue it throughout pregnancy, but you would not initiate a biologic. We don't have strong indication to initiate a biologic during pregnancy. So this table just shows that the mild, moderate, persistent asthma and what inhalers are indicated there. So I'm not going to go over that. It's basically the same as a non-pregnant patient. So again, this is the summary of the slide. So look at all the pieces of the pie. Start with monthly assessment of asthma. Go over patient education every time, avoidance of triggers, treatment of comorbidities, and then the pharmacological therapy for management of asthma. The preferred controller is inhaled corticosteroid, mostly buddhasenide, because that's most studied. The preferred reliever, this study had mentioned short-acting beta agonist. We can use the short-acting beta agonist or inhaled corticosteroids, but people have used a short-acting beta agonist for a while, so that's on this recommendation. Systemic steroids are indicated, same as in the non-pregnancy state. And again, if anesthesia is indicated during labor, this is something that we don't usually think about. Regional anesthesia is preferred. That's mostly because of upper airway edema, the physiological changes, decreased reserve, elevated diaphragm, so all those need to be kept in mind. As I mentioned before, the monoclonal antibodies and specific immunotherapy should not be initiated during pregnancy. An approach, I just want all the physicians here to think, to not go away with, am I the one that's doing all these five things in the pie? Is it all on me? So no. So we have, studies have looked at pharmacist-led medication management and also nurse-led management of patients with asthma, prospective studies. And you, a basic conclusion is, you can use your pharmacists and nurses, just like how you would work in the ICU in a multidisciplinary team. This is similar in the management of asthma patients. We can use our multidisciplinary team. So this study just looks at the asthma exacerbation, maternal asthma exacerbation on perinatal outcomes. As I mentioned before, the perinatal outcomes are not good if the mother's asthma is not controlled, so it's okay to use systemic steroids. One line about acute asthma exacerbation, beta agonists are the first line, the short-acting beta agonists, plus-minus anticholinergics, avoid maternal hypoxemia, continue to monitor the fetus, maintain uvulemia for the mother because they have physiological impairments. Systemic steroids can be used without delay, especially in asthma exacerbations, which are severe. You can use adjunct therapies, such as magnesium sulfate or terbutaline if needed. Early and expert intubation and mechanical ventilation. So intubation is one thing, continuing mechanical ventilation while avoiding auto-PEEP and hyperinflation, so that needs to be taken into consideration also. ECMO can be considered in extreme circumstances. Again, it's an experienced ECMO delivery center. So with that, I conclude my presentation of stable asthma during pregnancy. Okay, sorry, so you have to hear, listen to my voice again for the next like 10 minutes, I'm sorry about that. So Dr. Sodhi was supposed to give this presentation but she was unable to attend the meeting due to a family emergency and so I will be talking about her topic. Again, I'm sorry, like you have to hear my voice for the full half an hour. Okay, her topic was asthma across the lifespan, looking at how hormones influence asthma control. So Dr. Sodhi is the Medical Director of Critical Care Services at University of Wisconsin. So the objectives are to go over the complex interplay of sex and gender, what is sex, what is gender, how does it affect asthma, we'll go over that. What is perimenstrual asthma? And then the effect of specific sex steroid hormones on asthma. So we did not have an ARS set up for this but which of the following is accurate? Is estrogens during pregnancy, the estrogens can exacerbate both type two and non-type two inflammatory pathways in asthma? Okay, that's important to understand. So it's not just one inflammatory pathway, estrogens can exacerbate both. So when you look at asthma prevalence by age as Dr. Shaikh went over, for children below 13 years of age, as per this study, asthma is more prevalent in males but after around age 13, there is a flip and you see more prevalence of asthma in girls and then women throughout their lifespan when compared to men. And mortality too, as you see the mortality increases in women which is the darker, females is the darker line and males is the lighter portion. Not only the incidence and the prevalence increases, the mortality also remains higher in women. So now what is sex and what is gender? So gender is a learned social construct and it's pretty dynamic. Gender is not set in stone. Sex is a biologic, physiological and anatomical parameter. So the asthma control in patients would depend on their socioeconomic status, cognition, how much do they know about the disease, how much do they know about the disease and how much do they, what are their values, what are their attitudes, what do they think will help them, it could be a religious aspect as well. Health behaviors in asthma control, do they smoke, do they use drugs, do they exercise, are they watching their weight, so that's important. And exposure to secondhand smoking, biological fuels or occupational exposures also need to be considered. And again, there are studies looking at lungs, the biological markers, which is biological slash anatomical where the lung size is smaller in women, airway size could be smaller, and how sex hormones have an added influence on top of these anatomical variations. Genetics, proteogenetics and epigenetic markers play a role and pregnancy, as I went over, there is a whole slew of changes that happen during pregnancy. Not only lung disease, on top of asthma, they could also have some sleep disorders that need to be treated. And outcomes of all these totally depends on, leads to the health-related quality of life, hospitalization and mortality. So not just looking, again, the whole concept of this is not just looking at just one aspect of things, but putting all this into context and caring for the asthma patients. So what contributes to severe asthma is they've divided that into two big buckets, age and gender. And age, as we went over, lung aging, comorbidities increase as we age. And there's immunosense or like death of the cells over a period of time or inflammation over a period of time as we age, lung compliance decreases. And there's behavioral changes that I went over in the research. And behavioral changes that I went over in the previous slide, what are their beliefs, what are their attitudes. And when you look at gender, the hormones are one part of the gender changes that happen. What happens during puberty? What happens during the menstrual cycle? Is there any effect of taking hormone replacement therapy on the asthma control? And also looking at the inflammation. Inflammation, as we know, leptin changes happen in obesity. And not only the environmental factors, that includes smoking, childhood exposure, they can also influence the genetics of a person, which in turn influences the sex hormones, which in turn influences the gender and leads to severe asthma. So it's a very complex interplay. You can't just pick one and choose to treat that particular aspect. Okay, so before we move on to the hormonal changes, especially in women during pregnancy, it's important to understand the menstrual cycle. So in the first, the menstrual cycle here, this diagram is showing you from days one to 28. For the first 14 days until ovulation occurs, it's the follicular phase, and beyond that is the luteal phase. And as you see, the hormone levels here, estrogen is predominant prior to ovulation, but post, sorry, I should be using this. So that's this gray line here. Estrogen is prevalent prior to ovulation. And then post ovulation, as you see, that is this purple line, progesterone level increases. So that's important to understand. So from there, going on to perimenstrual asthma. So does asthma worsen during menstruation? Yes, there is cyclical worsening. It's a common condition. And in the perimenstrual period, because of the hormonal changes, there's increased bronchial hyperreactivity. As this, the same thing as the previous slide, it just shows ovulation happens here, and then progesterone increases. Prior to that, it's estrogen. So that has effect on your airways. And sex hormones, which is the first, the ARS questions, they cause upregulation of both Th1 and Th2 cells. So here, you see TSLP is up here. It's one of the alarmants. So the alarmants also increase due to the hormones. So IL-33, 25, and TSLP. And it totally, from below that, it activates both the Th1 and Th2 cells. This is kind of like a leeway to the future studies that could happen with all the biologics coming in the market. But they're not specifically studied in this population. So you could ask, so we spoke about estrogen and progesterone changes during the menstrual cycle. What about androgens? Does testosterone have a role in asthma management? So decreasing testosterone levels in men over 45 years has been shown to increase asthma prevalence. So if the testosterone is higher, increased testosterone, there's decreased asthma prevalence. And there's a dose-dependent relationship between the two. So testosterone's basically good for asthma control. If studies have looked into free testosterone levels, so the higher the free testosterone levels, the lower the asthma symptoms and the lower hospitalization in women. So here you look at the free testosterone level with the odds ratio of, I think that study, it was around one here in both these. So this study was done in 2020, published in Thorax. And the conclusion was free testosterone levels, higher the free testosterone levels, decreased symptomatology in patients with asthma. That's both men and women. So not just women, it's both men and women. And this shows the temporal relationship for the Severe Asthma Research Project, the SARP project that's pretty recent, from 2021. As the androgen receptor concentration increases, the FEV1 increases in both men and women. And that's what's shown here. So AR is androgen receptor. So as the receptor increases, FEV1 gets better and also the FEV1-FEC ratio is improved. And there's also a relationship between androgen receptor and pheno. And these are all basic science studies that need to be further explored. So now we can talk about, we spoke about endogenous hormones, what happens with estrogen, progesterone, testosterone. And now what if you give hormones externally? What about the exogenous hormones and conditions such as hormonal contraception? So there is mixed results for giving exogenous sex hormones and asthma control. They could reduce asthma incidence and decrease asthma-related healthcare utilization. But there's still, the verdict is out there to see what kind of hormonal contraception is more effective. There's no head-to-head studies saying one is better than the other. And while talking about hormones, it's important to say a little bit about our transgender patient population. There is very limited data. This large cross-sectional study of over 50 million patients looked at the transgender population. And they mentioned the higher incidence of asthma in transgender patients. Is it due to the hormones? We are not entirely sure, but there is a higher incidence in transgender patients. So in summary, we need to understand the sex disparities in asthma. Estrogens exacerbate the type two and non-type two pathways. That's important as we talk about biologics down the line. Androgens decrease or attenuate the type two and non-type two pathways in asthma. There is mixed results for contraception and hormone replacement therapy on asthma prevalence and incidence. And there's increased risk for male to female transgender patients. Is that because of decreased testosterone, increased estrogen? We are not sure, and that's, the verdict is still out there for that population. That is all with asthma and hormones. Okay, now I would like to introduce Dr. Conroy to talk about asthma in the elderly. Thank you, Dr. Ramesh. I'm Megan Conroy. I'm an assistant professor and an associate program director at The Ohio State University, and my pulmonary practice has a specialization in asthma. With our few minutes left, I hope to leave you with a good understanding of the challenges in diagnosing and treating asthma in an elderly population. This animated graphic shows the population by age and volume and is sequentially advancing over time. What's important to take away from this is that what has prior looked like a pyramid of age distribution with a smaller number of elderly patients and a swell of middle age and younger patients is really turning more into sort of a straight pillar with a little bit more even distribution of patients across age groups in the U.S. By 2030, one of five adults will be over the age of 65, and by 2050, the number of elderly adults is projected to double. So asthma in the elderly is of increasing importance, not just because we have an aging population, but also because we actually see significant challenges in the recognition, in diagnosis, and challenges in treatment with associated increased morbidity and mortality of asthma in the elderly age group. So what are those diagnostic challenges? There's a variety of things that can make it a unique challenge to diagnose asthma in this age group. People of more advanced age tend to have a reduced perception of bronchoconstriction when compared to younger individuals. This means that they may not have a good assessment of their own burden of asthma symptoms. Additionally, there may be a misattribution of symptoms, so a thought that their dyspnea could be a normal part of aging, and they may dismiss it or not seek certain diagnostic care for this. There is also a significant variability in elderly patients from sort of this fit to frail phenotype, and that may impact how their symptoms are received by a clinician working that up. Are they ascribed just to a part of normal aging in a more frail individual? There's also a lot of comorbidities, which can complicate the workup of dyspnea, impact their symptoms, and impact asthma control. And recognition of overlap syndromes, particularly with COPD, becomes important both in diagnosis and in guiding treatment. There is an underutilization of spirometry overall in the diagnosis of asthma, and particularly in the elderly. And there can be difficulty in elderly patients completing good exhalation maneuvers to get quality spirometry, which may make it harder to get good objective data to document that variable airflow limitation. Additionally, older patients with asthma tend to show less reversible airflow obstruction, and may require bronchoprovocation testing to document that airflow limitation variability. Lastly, patients may have misconceptions about the presence of asthma, and new onset asthma in adulthood, and that may change their care-seeking behaviors. As Dr. Sheik had shared with us earlier, the care of asthma in early years definitely impacts lung function over time, and as we age, and as we all know, smoking advances the loss of lung function. And what we can see here is that these green lines of a non-asthmatic smoker, and a blue line of an asthmatic non-smoker by the age of 60, often result in very similar FEV1, very similar lung function. And so our patients with long-standing asthma will, by advanced age, show reduced lung function that in some ways may mirror the loss of lung function that we see in smokers. As features of aging, there's a variety of changes which occur that alter pulmonary physiology. From a pulmonary standpoint, with age, we see increase in air trapping, a reduction in elastic recoil, and this all results in a reduction in airflow. From a musculoskeletal perspective, we see decreased chest wall compliance. This may be from age-related kyphosis, as well as decreased pulmonary musculature strength. We also see a variety of changes in the immune system, as Dr. Ramesh had mentioned, our immunosenescence, with cellular senescence contributing to less resilience to injury, increased fibrotic scarring, and we actually see an increase in inflammatory mediators and cytokines, which result overall in an aging lung and increased neutrophilic inflammation, but particularly in the asthmatic airway, we often have a change from T2 inflammation towards increased non-T2 or neutrophilic inflammation. In those over the age of 65, the burden of asthma symptoms may be greater. The prevalence of asthma is increasing among elderly at a higher rate than compared to other population ages. There's greater morbidity and lower health-related quality of life. Elderly patients see more and longer duration of hospitalizations, and aside from our very youngest pediatric group, those over the age of 65 have the second highest outpatient visits for asthma. As Dr. Ramesh shared, women often fare worse, and we see disparities among women in older age with higher hospitalizations and higher mortality compared to men. Incredibly disheartening, these disparities are even worse among our black and Hispanic Americans and among low-income patients. So this graphic shows the asthma death rate by varied demographics. Death rates overall are low, but we see disparities between men and women, disparities between black and white, and in our oldest age group really carries the highest burden of mortality due to asthma. Our elderly patients with asthma may be a variety of phenotypes. They may be the patients that have been in Dr. Sheik's clinic as children with their early-onset asthma, and with those many years of long-standing asthma are more likely to have severe airflow limitations, more likely to show incomplete reversibility, and are more prone to exacerbation. But we also, in this age group, have those who have adult-onset asthma over the age of 40. They obviously have a shorter duration of asthma. They often see less atopy, but paradoxically to that, often have a lot of rhinitis, and it's very common that in over 50% of adult-onset asthmatics, they report worsening rhinitis symptoms and a significant URI that preceded the onset of their asthma symptoms, which led to diagnosis. We see more obesity in this population, more tobacco abuse, and occupational inhalational exposures that are compounded over time, particularly when we think about things like cleaning products and those in cleaning industries that really impact their asthma control. So do we see phenotypic clusters similar to the overall SARP groups in the elderly population? This is a study from a Korean group looking at 872 elderly asthmatic patients doing a cluster analysis and described four different clusters here that did also correlate with the likelihood of asthma exacerbation, as seen here in this Kaplan-Meier curve. Here we see that those with longer-standing asthma, worse lung function, and smokers were generally more likely to show exacerbation. A similar cluster analysis out of a group from Michigan showed a description of four different clusters, and here they showed that the most differentiating features were high variability in pre- and post-FEV1 as well as the duration of asthma were the most differentiating features to their control. Unfortunately, disparities really do persist, and among this analysis of a survey results from nearly 5,000 individuals over the age of 55, even when controlling for income, education, health insurance, and comorbidities, black and Hispanic Americans were two times as likely to visit the ER, and they were less likely to report daily symptom control. So disparities are really, really significant, even in elderly age, that all of the social, societal, and structural factors that lead to these disparities persist into old age and can often be exacerbated by other social changes in older age. So what are the treatment challenges that come in for our elderly patients? By design, a lot of the evidence base that guides our treatment for asthma may exclude these patients, either by age or by smoking history, and 50% of adults with asthma have some smoking history, and so our evidence base guiding the treatment of these patients doesn't really include them. In addition, it's more common that we see undertreatment with inhaled corticosteroids among elderly populations. As I mentioned, we see an increase in non-T2 asthma, non-T2 inflammation, leading to increased neutrophilic airway inflammation, and this type of inflammation is inherently less responsive to corticosteroids. There's also probably a greater involvement of the smaller airways, and there's not a lot of great data to tell us about how that impacts drug delivery, and so is there benefit to using some of these smallest particles in inhalers? It's not exactly clear. There's a lot of things that may impact our patients' treatment adherence throughout their advancing age. Some of the things that can impact inhaler use, for instance, include arthritis and fine motor coordination that can make it really difficult to actuate a pressurized metered dose inhaler dose. Cognition and learning changes may make it hard to learn how to use a new device, and visual changes in inspiratory flow may make it difficult for that drug delivery to get there. All of these things making the already really difficult devices of inhalers that we prescribe to our patients harder to take, and drug delivery further threatened in elderly age. Other components that are not just the asthma and just the airway inflammation may make treatment of asthma in old age more difficult, with frailty and social isolation, economic limitations limiting access to medications, complex polypharmacy, the inclusion of things like beta blockers or aspirin in potentially aspirin sensitive patients, and comorbidities that increase in cardiac, osteoporosis, and cataracts in complicating their tolerance of inhaled corticosteroids, GERD and obesity in higher rates, sleep apnea, kyphosis, and aspiration, all of which can lead to worsening asthma control. And so all of the various comorbidities that are needed to keep a close eye on, and as a pulmonologist, aggressively treating your asthma patients really expands in the elderly population. And so taking a patient-centered approach to care with really multimodal consideration of a variety of these factors becomes important. But I don't wanna leave you with just sort of threat to that good comprehensive care of these patients can make a difference, and so this is a really beautiful study, the Samba study that was published in the New England Journal of, excuse me, JAMA Internal Medicine, looked at 391 asthmatics in New York City, and did a comprehensive and personalized intervention in these patients, looking at what are their risk factors for medication non-adherence, their risk factors for not getting access to medicine. They did coaching interventions, helping them to understand how to use their inhalers, understand their disease, and reduce even antigen exposures in their own home, so highly personalized, and did a lot of reinforcement over time. And they saw a statistically significant improvement in ACT scores, asthma-related quality of life, medication adherence, and reduced ER visits over three, six, and 12 months. And so good comprehensive care of our more advanced age patients with asthma has the ability to really impact their control, even with some of the physiologic changes that can make that more difficult. So it's important to remember that our morbidity and mortality from asthma disproportionately affects the elderly. We have a paucity of data in this age group to guide our treatment, and it's important to remember that comorbidities and multidimensional factors, as well as changes to the respiratory system due to aging, will change their response to treatment and change their control. Hallmarks of our treatment, though, are still the same. Good comprehensive care and control of comorbidities is incredibly important, and a personalized approach can make a large impact. And with that, we can take a few minutes for questions. Thank you all. Thank you.

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