Okay, good morning, and welcome to our session on Smart Therapy and Allergy Immunotherapy. I am joined by Dr. Mustafa, who's going to start our conversation, and Dr. Shahid is also joining us from pediatrics, and Jerry, tell me your last name, I'm so sorry. Krishnan. And Dr. Krishnan will be joining me in talking about immunotherapy. So we are delighted that you're here, and hope that you will benefit from some of the discussions that we will have after that, and certainly from the information that we're going to provide to you. So I'm going to start with Dr. Mustafa, who will be speaking about the pros of allergen immunotherapy. Good morning, guys. Thanks for joining. Thanks for the introduction, and thanks for the organizers, for the invitation. I mean, this is not a fair fight, though, the allergist in a room with a room full of pulmonologists talking about allergen immunotherapy, but I'm going to do my best to take the pro stance. I do allergy immunology in Rochester, New York. It's really had the doors open. I've never given a talk with palm trees in the background, so thanks for the invite. There's a simple objective. Why would you consider allergen immunotherapy for individuals with asthma? That's my only objective today, and it's to convince you that that may be worth doing. So we like guidelines. You guys know these asthma guidelines, right, the NHLBI guidelines? If you look at all these steps, what people don't read is the fine print, right? This is not a contract. These are guidelines. And the fine print, it says to consider immunotherapy for any asthmatic between steps two to four. So if you're into guideline-based medicine, which we can talk about, it's on the guidelines. I think an important thing to mention here is it doesn't say steps five and six. It says steps two to four. And that's important. We're going to talk about it, because we all know asthma's a syndrome, not a disease, right? And we're going to try to consider personalized care, so when do you consider it becomes the real question. If you like the GINA guidelines, same. It's right there. Consider immunotherapy in steps two to four. So these are guideline-based, and I'll give you some quick data on why it's in the guidelines. And I think the other point here is one of these suggests subcutaneous immunotherapy, allergy shots, kind of what we're most familiar with. But there is FDA-approved sublingual immunotherapy. You guys should know that as a pulmonologist, and I'm sure you do. And there's a lot of off-label sublingual immunotherapies, so the question becomes the nuance of what do you consider when. So why the heck would this work? We all know about the one airway hypothesis. The upper airway affects the lower airway. They're histologically very similar. There's good pro-inflammatory infiltrate in the upper and lower airway that's very similar. And then there's mechanisms of interaction, too, whether it's direct drainage, abnormal mucosa, or most interestingly, systemic propagation of inflammatory markers from the upper airway to the lower airway. I'm not an ENT surgeon, but if you do pulmonary function tests and blood work, CBC would differ differential on someone pre-op on their day for their nasal polypectomy, and then if you repeat it post-op same day, there's significant improvement right after you remove polyp burden. So there's certainly something going on up here that's driving systemic inflammation. So it's more than just a direct interaction. We use a lot of medications. We use inhaled corticosteroids for asthma. We use a lot of biologics, as we should. They're fantastically efficacious, well-tolerated medications. Not a single one of them, including ICS, are disease-modifying for your asthmatic. Allergen immunotherapy is disease-modifying. I mean, you can't argue with disease modification. We don't do that much in medicine. So what happens is we have very quick immune changes when you start someone on immunotherapy. Within hours, you'll see decreased mast cell degranulation. You'll stabilize mast cells. T cells will start. You'll start getting regulatory T cells over the course of days to weeks, and then the last thing you get is antibody changes. IgE will go down. IgG4 will go up. TGF-beta, IL-10, regulatory cytokines will change over time. So all of that is happening in your immune system. This is your standard kind of diagram for asthma, and these T2 cytokines, right? IgE, IL-5, IL-4, IL-13. These all have targets, but none of them are immunomodulatory. None of them are affecting your immune system. None of them are changing your immune function over time. So the opportunity to disease-modify someone's asthma versus treating symptomatically I think is a huge upside when you're considering immunotherapy. As an allergist, immunologist, Dr. Sheikh also, we see kids and adults. If we want to talk about disease modification, I'm a big fan of prevention rather than treatment. If we can prevent things, that's always better than treating things. This is a landmark study. It's an old study now. It's from Journal of Allergy Clinical Immunology in 2002 of individuals, children with allergic rhinitis. So 205 children with allergic rhinitis, age 5 to 14, half were put on immunotherapy, half were not. They were treated for their allergic rhinitis per standard therapy. This was done in Europe, followed out over three years, and what you see is the folks with just allergic rhinitis, no one had asthma in enrollment. If you were putting them on allergy shots, you decrease their likelihood of developing asthma by two and a half fold. So now this is prevention of asthma trial, PAT study. So we're now preventing asthma before it even starts in a population that's at high risk for asthma, and we obviously know the comorbidities of allergic rhinitis and asthma. So if you're seeing children in the United States, our treatment paradigm is a little bit reactive. You put them on some loratadine, which doesn't work. You put them on fluticasone. You mess around with some other meds. Their allergies are terrible. Then you consider immunotherapy. In Europe, they lead with this much sooner as disease modification rather than just treatment of symptoms. So proof of disease modification in a pediatric population, and we have windows of immune tolerance. When you intervene with immune therapies is very important, and kids are much more plastic than adults. So again, it's not for everyone. Who are you treating and when should you think about it? There's too many studies. Allergy shots work, so you should use them for asthma is obviously my message. There's too many studies, but there's a Cochran Review. It took 88 studies with folks with subcutaneous allergy shots, not sublingual immunotherapy, and it didn't look at their outcomes for allergic rhinitis. It looked at their asthma outcomes, symptom scores, medication, and bronchial hyperreactivity and decreased system medications. And what you see is this grid. There's a lot of happy faces on there suggesting that immunotherapy was efficacious for these folks with asthma, for their asthma outcomes. There are a lot of unhappy faces on there, and that's from the local reactions from immunotherapy. Shots hurt, right? Shots have local reactions, but systemic reactions, clinically meaningful reactions, we'll talk about. So most of these happy faces are from asthma outcomes. The red are from side effects. We work a lot with trainees. I think important is the juice worth the squeeze for your therapy, right? What's the number needed to treat for a statin to prevent a cardiovascular event, stroke or heart attack? It's 40. It's pretty good. You got to treat 40 people with Lipitor to prevent one. In this study, the number needed to treat with immunotherapy to prevent one meaningful asthma exacerbation is four. That's really good. What's it look like compared to our other asthma therapies? It's the same as an ICS. That's really good. It's depending on the population, you look at significantly better than LABAs and certainly better than LAMAs, all medications we all use and we should use. So I think the point, again, depends who is the right candidate for immunotherapy when you're managing their asthma. We talked about that Cochran review and all those sad faces, right? But this is clinically meaningful side effects for immunotherapy. It's non-pharmaceutical. It's disease modifying. The biggest side effect is risk of systemic reaction. And for you guys, I mean, the takeaway is about one per thousand doses that you administer, you're going to have a systemic reaction requiring epinephrine. You're injecting someone with a fixed dose of an allergen. So if you give a lot of allergy shots like an allergy office does, you'll get a couple, you know, this is going to happen in your office, but the rate is one per thousand. And if you look at AEs with medications, I think most of us would sign up for side effects of one per thousand. So fantastically safe. We talked about immune modulatory. We talked about efficacy. So what are the reasons not to do it? I mean, this is a safe, effective intervention. Cost comes up. It's not cost effective. It's really, you know, it's a long three to five year course. If your patients are on allergy shots for 20 or 30 years, they might want to check out a new allergist. There's good data. It's three to five years, but it is cost effective. So this is retrospective study of 20,000 individuals with asthma, 5,000 were on immunotherapy, 15,000 were not. This is obviously records. It's from the state of Florida. And it looked at their health related cost of care. And the folks on immunotherapy consistently had less cost of care compared to counterparts who are not on immunotherapy. And that's because immunotherapy ends up being medication sparing. You end up using less medications. And we think about biologics being expensive, and I'm going to touch upon that. But inhalers, nose sprays, antihistamines, these add up as well. This is ICER data on biologics. We use them. We should use them. I use them a lot. We have 728 patients in our practice on biologics for asthma. Last we checked. And they're expensive. So we're certainly happy to use these medications that are effective and expensive. ICER would say most biologics for asthma are not cost effective, and you would have to decrease the cost by 40 to 60% to make them cost effective for asthma. And I think that speaks to the heterogeneity of the condition of asthma. But immunotherapy has been shown over and over again to be cost effective. So the key is no one's arguing that allergy shots or sublingual immunotherapy should be used for everyone in asthma. We need to individualize care. Who is it, right? It's folks with, obviously, bless you, you need to see an allergist. It's folks with allergic sensitizations, maybe seasonal variations. A T2 signature, and I would argue on the younger side with milder to moderate asthma. I don't think folks with severe asthma, you're going to get much efficacy with immunotherapy. So we're not talking about the same population that may benefit from biologics. It's a mild to moderate population. Maybe younger. As I get older, my definition of younger keeps changing, but we're talking about younger. Certainly PEDS has more efficacy than adults, I think, certainly with disease modification. They do have symptoms of rhinoconjunctivitis. They may have seasonal variation. You guys know about the asthma epidemic in mid-September, right? Where you get viral infections hitting with ragweed in the United States, and you see a spike in asthma, ED visits, hospitalizations. So immunotherapy can be very efficacious when you're taking that history. So in summary, it's certainly guideline-based. It's disease-modifying, which no other therapy for asthma is. It works, not only for allergic rhinitis, but it works for asthma per lots of reviews, meta-analyses. It's well-tolerated with a consideration for systemic side effects, and it's cost-effective. So why would you not consider allergen immunotherapy for management of asthma? We'll find out next. Thanks for listening. Thank you very much. How many in here are pulmonologists, as opposed to allergists? How many allergists do we have? Okay. You get the patients because we send them. So they've been primed before they come to you. So what we're going to talk about in the next 10 to 15 minutes is some of the things and some of the discussions that we've had with our patients. I also have the luxury of having given this talk at ATS, and it's amazing how basic the cons are. So let's talk about that. Okay. Now, I'm also going to give you a couple of extra slides because a lot of these discussions are going to be so common that it's going to be very helpful to you. So we're going to talk about barriers to immunotherapy, cautions and contraindications. All right. Everything we look at is risk-benefit, and those are the discussions that we have with our patients. And clearly I have no issues with all the things that were said and all the things that tell us that allergen immunotherapy in selected asthmatics is a good thing. So this is the EPR-4 recommendation, came out in 2020. And there were really only two sets of recommendations that came out of EPR-4. And we'll talk about those as we go along. But the recommendation is for 5 and up, mild to moderate allergic asthma, and it's a consideration for allergy immunotherapy. And we all know how we pick those kids out of a crowd. So the topics that we're going to discuss in these next few minutes are the impact of age, access to allergens, to allergists, specialty limitations, costs not only in time but in money, issues of insurance, eligibility, authorization, biomarkers, AEs, and then contraindications. So we have a lot to talk about in this short period of time. So is there a minimum age to give allergy shots to kids? Well, you've all heard discussions about parental permission and child descent. The kid's got to sit there. They're not going to get to the allergist unless their parents bring them. And they're not going to stay if the kid's not going to sit in the chair and allow them to give the injections. The child has to be old enough to cooperate with those injections. And the other thing they have to be able to do is to tell you when they don't feel right, if they're starting to have a reaction. So they do need to be able to communicate. So for those who can't, that's an important piece. At the other extreme of life in the elderly that they consider either 60 or 65, depending on who you read, there is no upper limit. But the allergy immunology people believe in the concept of immunosenescence, which gradually has been coming out of the lexicon. However, comorbid conditions and medications that the elderly may be taking can increase poor outcomes, systemic effects. And remember that drugs like beta blockers will decrease your response to epinephrine. So should you have a hypotensive effect, a side effect with anaphylaxis, it may be very difficult to treat. Okay. The next part is a very interesting paper that I found in my search for this talk. And that was access to care. There aren't that many allergists around. I'm from New York. I thought they were on every street corner and every hospital and every place. They're not. If you look at the map that you'll see on your left-hand side, you'll see that although there were providers in every state, when this group of authors looked at the data, they found that 81.5% of counties in the United States had no providers. And if we look at how far it takes on the other side, the maximum distance for people who live in Nebraska was 211 miles to get to an allergist. Now we know not only did we want them to get the shots, but they need to be monitored, they need to be in a place where they can be supervised, and very importantly, where they cannot be adherent to care and be educated. Now where do allergists live? I'm going to show you, and work. If you look at that map again, you'll see they like urban areas, they like the East Coast, and they like patients who can pay the bills. So if you look at these, you'll see that allergists tend to work in areas that have higher incomes, and they quote them here as a difference between 58,000 and 47,000 in general as a yearly income. So the median incomes really do impact on access to care. Now what is this going to cost you? Well, you have to pay the provider. The insurance company has to be approving the allergist. There are co-pays, there are deductibles, there's self-pay. And in the elderly and the Medicare population, it's very interesting. A co-pay of a dollar can make a big difference between having enough to eat, feeding your children, or coming for shots. Now this is a study that was done by the American Lung Association, and they were looking for barriers to care, to guideline care. And they were talking about insurance for the state Medicaid, and this was all the 50 states, District of Columbia, and Puerto Rico. And out of this, I only pulled the two sections, the one on allergy testing and the one on allergy immunotherapy. And you can see that the specialty visit limitations are important. You have to get to the allergist before you can get the shots. And the co-payments are a big problem. These are, you know, 39, 35 to 39%. And so it's a significant cost not only to be tested, but also to be treated. And if you look at it over time, as you've just seen on the earlier presentation, overall, there is a cost savings. But most times when you look at the money that you make in your own divisions, it doesn't account for the downstream effect of hospitalizations, referrals, treatments, and any kind of imaging. But when you do have people who take a longer look at that, you do find significant advantage. Now one of the things that you'll also see is that people not only object to the money, but they object to the time they have to spend. So your initial evaluation, your history, your physical, your laboratory can take a couple of weeks altogether. There's a buildup in the maintenance phase. As we've already discussed, it takes about three to five years. But the buildup phase takes shots a couple of times a week. And then they space it out over time. But, you know, life happens. You know, you have to go to work, you have to take care of your kids, your kids have football, baseball, dance, and, you know, the shots don't always come on the top of the list, although I apologize for that. And then there's post-injection monitoring. The recommendation is at least 30 minutes, because most of your AEs will happen in those first 30 minutes. And then you have your travel time. So it's a very significant time commitment. So when I'm talking to a parent, most of the time their question is, well, how do I know this is going to work for my child? It might work. It might not. Do I have a biomarker? I don't. And the biomarkers that are available are very limited. And for the most part, they're used in research settings. And so in order to figure out whether this works, you have to use it. So let's look at adherence. How good do you think it is? Well, in the first year, it's pretty good, because you spent all the money to learn how to do it, to know how it works, to know that it's going to work for you as a potential. But there are lots of things that happen. So if you miss your allergy shots, there's reduced effectiveness. And the dropout in the first year is associated with decreased effectiveness. And that's pretty common sense. But in saying this, we know that you're going to use a lot more resources, have a lot more cost, increased hospitalizations, increased morbidity, and the potential for mortality. So if you're going to do this, it's a good idea to do it. Adherence is clearly better in children than it is in adults, because they're physically brought there. Now, I thought this particular study was very good. It was done for subcutaneous immunotherapy. And they wanted to know why people drop out. And it's fairly clear from what I told you before. Most of them drop out because of money. Now, this is an American study, and it was done by Vaswani in 2015. And just to show you that it doesn't matter what year it is, what country you came from, the expense is a major issue. This is one from Giovanni Panjo out of Italy. And almost 40% of those patients dropped out because, or 40% of the patients who dropped out cited expense and time as major considerations. So let's talk a little bit about side effects. The most common one is going to be local. Up to 86% of patients receiving subcutaneous immunotherapy are going to have local reactions, redness, swelling, itching. And most of the allergists take care of that with a little hydrocortisone cream. The larger reactions, whether the larger local reactions predicate or predict what's going to happen in terms of larger systemic reactions, it's hard to say. The data on that is really variable and can be a challenge when you're discussing it with patients. But there's always the risk of a systemic reaction. But the risk is small. This is what the statistics look like. They're fairly similar to what was presented to you before. But the part that I wanted to bring up to you is that acute asthma attacks occur in 50% of those severe reactions, which is one of the reasons why when we talk about risk factors, we talk about uncontrolled or partially controlled asthma as a major risk. And here you can see some of the risk factors for fatal systemic reactions. The most common one is going to be uncontrolled asthma. I changed the colors as we switched here just so that they were a little clearer for you. If a patient is pollen allergic, you don't want to be giving him increasing doses necessarily if it's in peak pollen season. Dosing errors are not common, particularly in supervised settings in allergy offices. But there have been a number of reported systemic side effects because patients weren't properly monitored or dosed. Some of the other risk factors are inadequate observation. And as I said before, most of your reactions will happen within the first 30 minutes. I'm going to skip to this one. This is a study, if you haven't taken a look at it, it's by Pitsos on clinical contraindications of allergen immunotherapy. He looked at 51 national studies looking for consensus guidelines. And then he also looked at international guidelines and tried to pull out some of the things that are absolute and relative contraindications to the use of allergen immunotherapy. The couple that I'd like to bring up to you in particular, we talked about the uncontrolled asthma and the partially controlled, is cardiovascular disease. It's much more common in the elderly and the adult population. And so for some of them, like the beta blockers, some people would like to take them off it. If you can switch it to a safer drug and still get a good response, the time is five to seven days. But as the allergists are taking more control over the referrals and the evaluations and the treatment, we're starting to see less in terms of these side effects and they're stretching the limits where if they know what these patients are taking, they're adjusted ahead of time. Psychiatric disorders, not only the disorder itself, but many of the medications that are used are important to take care of. Okay, let's talk for a minute about the sublinguals. They come in two forms, they can come in tablets or they can come in drops. And the recommendation is against the use of sublingual immunotherapy for asthma treatment. This is mostly because there's not a lot of good data. When you start to look at the studies, you're going to find that the outcome measures that they're looking at are also very variable. We know it's a heterogeneous population. So I pulled the pros and cons because I can argue either way with double negatives in terms of this presentation. The pros, when you look at sublingual in general, it's convenient. You can do it at home. It's comfortable. There are no shots. And there are fewer systemic allergic reactions. And I don't have good data to say whether that's truthful for patients with asthma. So the allergy drops themselves are not FDA approved. There are tablets, however. A lot of the data was done, a lot of the studies were done in Europe where they tend to use one allergen. The American allergists tend to use more in one injection. Remember that all of these, whether we choose sublingual or subcutaneous, require that you're consistent. And when you look at the data on adherence for patients with SLIT, it's much lower. It's great for the first year, but it's down to about 44% after the first year. Okay. Now, EPR4 was 2020. So it looked at data that went up to 2018. Gina comes out every year. And when it came out in 2022, this is the update that they gave. So this is the most recent one. So for adult patients only who have allergic rhinitis and are sensitive to house dust, have persistent asthma despite their inhaled corticosteroids, and have an FEV1 that is relatively normal, you can consider the sublinguals. Okay. And this is the most recent of the meta-analysis and review from Cochrane. And you can see that we just don't have enough data. So studies are certainly important and we'll watch, it will be evaluated for this year's upcoming allergy immunology review. So what's the downside? It costs a lot of money. It's going to take you a lot of time. It might not work. There are no biomarkers that are going to help me. Poorly or uncontrolled asthma is a risk factor for systemic reactions. And the risk of anaphylaxis, although small, is real. So every parent will help you to choose wisely. Thank you very much. Good morning, everyone. My name is Jerry Krishnan. It's a pleasure to be with you here today. I'll be giving the pro version of the SMART talk. It'll be followed by the con, and then hopefully we'll have some time for some discussion. Here are the objectives. There's a lot of terminology and acronyms I thought would be worth having an initial conversation, specifically pay attention to SMART versus AIR, A-I-R. That's a terminology you're going to be hearing more about, and people often get it confused. There's some very unique features of formorterol. So everything I'm speaking about, when I say SMART, is about the use of formorterol as the LABA. It does not relate to other LABAs. So be careful about that topic. Second, we'll talk about what the recommendations are from the NAPP and GINA. And then last, we'll talk about what is the actual evidence. I have a number of disclosures, which I've previously reported. So let's get on with the talk. Everything I'm talking about is actually in these documents, but obviously these are hundreds of pages long and really not all that digestible for most cases. I was both involved in the NAPP as well as GINA, so we actually ended up having a joint report that was specifically about SMART. I would encourage you to read that report if you want some more details after the session today. So first, terminology. When we talk about reliever in the asthma guidelines and other reports, we're specifically talking about taking medications as needed in order to help relieve some symptoms. It could also be in the context of use prior to exercise or allergen exposure. For example, if you're gonna go visit a friend who you know has a cat and you're allergic to cats, which is me, by the way, I'm allergic to cats. Controllers, this is a different term. This really, the idea here is that you're addressing both components or both domains of asthma control, meaning you're trying to help reduce symptoms but also the risk of future exacerbations. So when we talk about controllers, think a little bit about essentially helping people feel better today and preventing exacerbations down the road. In most cases, when we talk about controllers in the year 2023, we are talking about inhaled corticosteroids. The other controllers that we've used in the past, you know, mast cell stabilizers, leukotriene modifiers, they're much, much weaker for asthma. When we say maintenance therapy, we are specifically talking about the regular use of a medication, okay? So daily once a day or daily twice a day, that's what maintenance refers to. So controller and maintenance therapies are obviously related because often maintenance therapies are intended to control current symptoms and prevent future risk. So keep that in mind and how you separate them. Okay, onto the acronyms, because I think you'll hear about it in the con. So I thought I would first clarify a couple of the terms here. So when we say SMART, it's an acronym that actually stands for Single Maintenance and Reliever Therapy. And it is the preferred term for the U.S. National Institutes of Health and the National Asthma Education Prevention Program. And the idea here is that you have a single inhaler device such as, very specifically in the United States, ICS for Mortarol, that's used both for maintenance therapy, meaning regularly scheduled therapy, in addition to as a reliever, meaning you take it as needed. So it's a single inhaler device that's used for both purposes. Just carry one device, helps you with both. The idea here is that it avoids confusion among patients about which to use. I think we've all had specific individuals in our clinic that's confusing, is it the blue or the red? And then you go on to see that the red inhaler could be a maintenance therapy, could also be a reliever therapy, so the colors don't help you at all, right? So the idea is just to bypass all that and say this is one inhaler that's both for maintenance and reliever. MART is just like SMART, in fact, it's equivalent. It's just the term that Gina prefers. So MART and SMART are the same thing. MART per Gina is that the idea, the reason why we chose to use MART is because some individuals actually have two inhalers, one they use at home and one they carry with them in a bag or in a purse or leave it at school. So the idea is that it's not a single device, it's actually two devices, one's at home, one's at work, school, wherever they're traveling. So for that purpose, they prefer MART. But the exact same thing, MART and SMART are the same. The other point to make is that, while I'm gonna tell you about the data to support the use of ICS-4-Moral, ICS-4-Moral is not FDA approved for that indication. Currently, ICS-4-Moral is only FDA approved as maintenance therapy. But I'm gonna show you the substantial evidence to talk about the benefits as maintenance and reliever therapy. And then finally, AIR. Again, that's a relatively new term, especially in the US. It's been used in Europe and Australia and other locations more often. But AIR has to do with anti-inflammatory reliever. Think of it as the reliever therapy that happens to have a steroid in it. You only use it when you need it, you don't use it as maintenance. And there is now, in the United States, the first ever approved AIR therapy, it's Budesonide Albuterol. Sometimes you might know the trade name, AirSupra. But basically the idea is this is Albuterol mixed with Budesonide and you can actually use it as reliever therapy. You carry that with you. Every time you can't breathe, you take two puffs of Budesonide Albuterol, wait a few minutes, if you don't feel better, take another two puffs. That is the FDA approved version in the US. In other parts of the world, there are other formulations, including ICS-4-Moral formulations, but it is currently not FDA approved for use of AIR using those formulations. Okay, on to 4-Moral. 4-Moral is a very special drug. If there's one takeaway from my entire talk, it's about 4-Moral. 4-Moral is different from other LABAs. And I think we've all seen some confusion where people write use of ICS-LABA and they don't realize that there are many formulations of ICS-LABA. Most of them do not include 4-Moral. So you're kind of inappropriately prescribing actually. So when you talk about SMART, you're talking about ICS-4-Moral formulations. In the US, there are two FDA approved medications, but they're not improved for this particular indication for that. The reason 4-Moral is different is that it literally is a hybrid. It has SABA-like effects, short-acting beta-2 agonist effect, think albuterol-like effects, helps you breathe better within minutes. And then it also has LABA-like effects, meaning that it lasts for many hours, up to about 12 hours or so. 4-Moral is a very special type. I've been saying this a few times just to drive the point home. It's a very special type of LABA. All the other ones we use in the United States, salmeterol, for example, do not have the short albuterol-like effects. So you can't take, let's say, fluticasone salmeterol and use it in SMART. It won't work. In fact, you're likely to end up with toxicity because by the time the person feels better, they've used a lot of ICS salmeterol, okay? So in SMART, only ICS formorterol. It also turns out that formorterol has its limitations. It doesn't work as long as now what's available, which are ultra-long-acting beta-2 agonists, such as velanterol. So formorterol, special type of LABA, it acts like albuterol, and it also has long-term effects, but it only lasts for about 12 hours or so. Therefore, whenever talking about SMART, be very specific that you're talking about ICS formorterol. Okay, on to guideline recommendations. NAPP has been mentioned a few times, so has Gina. I'll present both of you today sort of the money slide, so to speak. This is the NAPP table. That's the table we all look at. It's hundreds of pages long, that document, but I suspect this is the only table most of us look at. It basically shows you the step care as it relates to asthma, and this is all about age 12 years and above. Step one currently, at least per the NAPP, when it was published in 2020, continues to recommend PRN-SABA. I suspect with the next iteration, it'll get changed to the albuterol-budazenide I just mentioned to you, which is now AIR and is FDA-approved. So currently, NAPP recommends SABA, but this will get modified. Step two is basically when you start the first controller. You can see here that you're introducing inhaled steroids. Steps three and four is actually where SMART is being discussed. It's basically moderate to severe asthma or the milder end of severe asthma. This is where you're using daily and as-needed ICS for mortarol. Steps five and six, that's when you start adding additional controllers and you start to think about biologics. If you look at Gina in 2023, as was mentioned earlier, it's published on a yearly basis, just came out about a couple of months ago, that you can now see that Gina is different from NAPP in multiple ways. One of them is that it's actually collapsing steps one and two. Gina's view is that it's not clear there's such a thing as mild intermittent asthma. Either you have mild asthma or you don't. In most cases, I think we all know that asthma doesn't come and go. It's there all the time. It may be worsened on particular days, but this concept of intermittent asthma is probably something we're gonna get away from in the coming years. Certainly, Gina has now removed it. You can also see that Gina only has five steps just to simplify things. So think of Gina as five steps, similar to the NAPP six steps, but it's starting to look a little differently, particularly on the mild end. Now, you can see here where SMART comes in for both NAPP and Gina, steps three and four is where SMART is used. Once again, ICS-4-Motorol on a regular basis in addition to additional doses if you can't breathe. AIR is only currently right now in Gina, and you can see here, it's the use of, in this particular case, ICS-4-Motorol. This was published before the albuterol budesonase was reviewed by Gina, but eventually albuterol budesonase will be added here as well. AIR and SMART are two different things. AIR means you only take the medication as needed. You don't have maintenance therapy. SMART, you've got maintenance therapy, meaning a regularly scheduled use. On top of that, you may take additional puffs if you can't breathe. So what's the data? This is the single slide. This is 30,000 people worth of data on one slide. So SMART with ICS-4-Motorol, what we know reduces severe exacerbations as defined by the use of systemic steroids for three or more days, emergency department visits or hospitalization versus SABA for earlier therapy, or actually, it turns out in a single study, 4-Motorol for rescue therapy among individuals 12 years and older by 20 to 30%. It's a pretty substantial reduction in the risk of severe exacerbations. In addition, what we know is that Budesonide and 4-Motorol are additive, meaning that if you look at the curve by the study by Rabay et al. published in Lancet in 2006, they literally compared SMART therapy versus SABA alone for reliever therapy versus 4-Motorol as reliever therapy. In each case, SMART was better. So SMART, there's something about the combination of inhaled steroid and 4-Motorol gives additive benefits. Okay, so how do you prescribe ICS 4-Motorol for reliever therapy, and what about excess use, which is what my colleague is gonna speak about next? First is that in individuals 12 years and older, we should be using the 164.5 microgram formulation of Budesonide 4-Motorol. In step three, you have two options. You can start them as one inhalation once a day or twice a day. Notice what I said, one inhalation once a day or twice a day for maintenance, regularly scheduled, and then on top of that, one inhalation as needed for symptoms, okay? And the reason is we're moving towards the fact that if people need it, they'll use more of it, they'll end up getting more steroid along the way as well. This idea of having a fixed prescribed dose every day, every month, all throughout the year probably doesn't really fit asthma. Asthma has worse months and not so bad months, so the idea is let the individual's request for more reliever therapy drive how much inhaled steroids that they're using since the medication is combined. If you're in step four therapy, we recommend two puffs or two inhalation twice a day plus one inhalation as needed for symptoms. Notice that the reliever dose for SMART is one inhalation, not two, and the reason for that is that most often, one inhalation's enough, and if you have two inhalations each time, you may overdose on the formorderol component, giving people jitteriness and tachyarrhythmias. So remember, SMART is one inhalation as needed, not two inhalation as needed. In randomized clinical trials, we've seen that participants enrolled in these trials and randomized to ICS formorderol, in most cases, they use zero puffs of their reliever or one or two, so relatively few puffs. In the randomized clinical trial by Patel et al published on Lancet Respiratory Medicine about nine years ago or 10 years ago, the days of excessive use of ICS formorderol as defined by more than 12 puffs is actually less common compared to excessive use of SABA, which was defined as 16 puffs per day. So this idea that if you give people a single inhaler, you ask them to use it for maintenance and reliever, they'll overdose consistently on that is actually not borne out by the studies that have been done and most of us who've used this in clinical practice will tell you the same thing. It doesn't happen as much because people actually feel better. Now, are there chances somebody will overuse it and get in trouble? Absolutely, but I think you can say that for any medication that is being prescribed. So thank you very much. I'll pass this on to my colleague and depending on what happens, I may run out the back door. All right, it's very hard to talk against the guidelines. So I will try my best and not to look like a old guy who doesn't want to change. So having said that, I just wanna start it from a saying that in my med school, we used to have a motto which used to say that enter to challenge what is known, not to worship it. So having said that, let's talk about that though the smart therapy is an excellent therapy, why it is not picking up as fast as we expect it to be and what can be the limitations and how we can address those. Now, I have no financial relationship to disclose and no copyright infringement is intended. So I'll start with my talk by simply accepting that smart therapy is recommended as it is effective and it is simple and there is no doubt about that. But the objective of this session is to highlight limitations and barriers in implementation of this therapy across the board. The most important part of these guidelines and any guidelines is that if your patient is doing fine, please leave him alone. Do not try to be the perfectionist because at the end, the outcomes may not be what you desired. So what are the possible or practical limitations? I don't think we have a time to go over on each one of them in more detail but just naming few of them. First of all is cost because inhaled steroids container is about $250 and any combination medication is about $500. In United States and someone is paying for it. There is no FDA approval for acute care use of smart therapy. It is off-label use. So we have to make sure that when we are prescribing it, we tell the patients and the families that we are doing off-label therapy to make sure that there are no legal implication if something goes wrong. There are and probably will still be lot of insurance related issues because in United States, the healthcare is dictated by insurance companies and pharmaceutical companies but we'll come to that in a minute. With this therapy, multiple inhalers might be needed every month. Private insurances may have a problem and they do have a problem because it is not FDA approved therapy and with the pharmacies dispense multiple inhalers every month. Then comes the education, the most important part, education and disclosures for the families and also for the healthcare providers because throughout our lives and in fact, for two generations, we have been educating not only the patients but also the healthcare professionals that these are the two inhalers. Use this every day, rain or shine. Use this only when you are sick and still about more than half of our patients do not know how to use these inhalers. Now we are telling them, combine them in one, use as you please but please do not use it more than eight times or 12 times in a day. After that, go back to your short acting beta agonist and run to the emergency room. So imagine how much confusion it might be creating in those who are not as, what do you call, educated in using these inhalers and that can cause a lot of issues. Then of course, the complexity of the therapies itself and for example, some of those might be it is only in outpatient settings, in the hospitals or emergency rooms. I don't think they prescribe smart therapy. They go back to their regular guidelines. There's always a risk of overuse, may not mean everyone but how many patients each one of you have in your practice who you are not sure, they'll follow your recommendation. That if you tell them use only 12 puffs after their stop, they will do it all the time. What if they use more and if something happens, who will be legally responsible for that? We know that in other long acting beta to agonist like salmeterol, some people have noted issues with the QTC and with the arrhythmias with overuse. We do not have too many studies to say that overuse of other long active beta agonist is safe. Most of the studies which were done were done with the different doses or different preparations and while in US, we primarily use MDIs, especially in pediatrics and are they both equally effective? Do relying on smart therapy leads to that delay in giving oral steroids? Because studies have shown if you give oral steroids early in the acute severe flare ups, you can decrease the hospital admissions or emergency room by about 30 to 50%. But we do not have a study which shows that if the patient on a smart therapy and another patient who is not on smart therapy and on short beta agonist, they both show up in the emergency room, what are the odds of each of them getting admitted? We know there are less number of hospital admissions in smart therapy because they are less likely to have a severe exacerbations but if the flare ups are not controlled, then what are the odds of getting admitted? Are there any different? There are no studies on that. Now, is smart therapy as effective in mild asthma as it is in moderate to severe asthma? And then what about the beta receptors? What about the polymorphism? What about the receptor saturations? We have known that if the receptors are saturated, the effect of the short acting beta to agonist is decreased. So we know that all long acting beta to agonist, including formaldehyde, have a strong bond with the receptor which lasts up to 10 to 12 hours. Once the receptors are saturated, what is the PR and use of long acting beta to agonist will show and how effective the short acting will be in those scenarios. So will it be causing more liability? We do not know those. So all these things need to be answered before we blindly accept that this is the best and the only therapy which mankind can offer to asthmatics. Now, I'll ask you, how comfortable you are in refilling two, three inhalers every month for all of your asthmatics or delaying oral steroids when someone have a severe asthma flare ups or prescribing smart therapy to the patients who have a poor perception of their own asthma and using smart therapy in intermittent asthmatics? Now, at the end, I will just quickly focus on mild asthma because there's a lot of change going on which suggests that intermittent asthma and mild persistent asthma are practically the same thing. So we just call them mild asthma and the guidelines on those are changing. Now, GINA guidelines, as we know, recommend against the as needed use of short acting beta to agonist in mild asthma and instead recommend that in younger children, we should use as needed inhaled steroids plus short acting beta agonist. But in children above 12 and in adults, we should start with as needed inhaled steroids and formaterol on everyone with asthma or everyone with mild asthma because they do not differentiate between mild persistent and intermittent. The theory behind it is that everyone with asthma can have severe exacerbations, can go to the emergency room, so it's at risk, so they should be treated with the steroids, not just with the short acting beta to agonist. Now, these are, as Jerry have mentioned it even more clearly than I can, in six to 11 years old, there's no intermittent asthma anymore. Mild asthma is mild persistent and intermittent combined together. In older, same thing. The US guidelines have not said this because they have not been updated for the last couple of years. There's a good chance that when they get updated, they may also change. Now, is that the right thing to do? It might be for many patients, but I do like to mention a small study which was published just a couple of months ago in Pediatric Pulmonology, which was done by Hal and his group from Texas Children's. Their aim was to determine the risk of asthma hospitalization and emergency room visit for Texas Children's health care patient members, which was about half a million with an asthma diagnosis and who have less than two short acting beta agonist canisters dispensed in a year, which by definition is a intermediate asthmatics because if you follow the rule of two. And there was about 45,000 patients in that group. They also screened those patients to make sure that it do not have any oral or inhaled steroids prescribed and no emergency room visit or hospital admissions for asthma in one full year. So they were even more stringent than the classical intermediate asthma description. Then they looked at those patients for next one year and look and see how many of them were hospitalized or had a emergency, sorry, emergency room visit. Out of those 45,000 or so children, they noticed that those who did not have a short active beta agonist prescribed even for a single inhaler, in a follow up year, the hospitalization was about 1.1 per 1,000. But in those who had between one and two albuterol canisters fulfilled, the hospitalization was 1.5 per 1,000. They both were not statistically different. Emergency room visits were 1.6%. They also noted that the children who were less than six years old had most of the hospital admission, which was 2.2 per 1,000, compared to one third of them, 0.7 per 1,000 in those above six years of age. And it is well documented in other studies also that during the first five years of age, the children have the most hospital admissions. After that, from six to 11, they dropped by one third. And then from 11 to 18, they dropped for another one third. Then they looked at the risk assessment, risk reduction assessment of NAEPP guidelines, which was about 0.77. And they applied that to this cohort. And they noticed that even in kids less than four years of age, which are at a highest risk of getting a hospital admission, you have to treat about 2,900 children to avoid one hospital admission in this group, which means that if the average cost of an inhaled steroid is $250, and only one inhaler is needed in a year, it will cost you about $700,000 to prevent one hospital admission in this group. And the older children have much lower hospitalization rate, about three times less. But even if you apply this higher hospital admission rate to that group, the cost will be about $1.5 million to prevent one hospital admission in that low-risk group, which I think is a little too much. So we do have a subgroup which is the low-risk patients. And in this cohort, there were those using less than two inhalers in a year of short-acting beta agonists, had no hospital admission or emergency room in the previous year, and have now required oral and inhaled steroids. And in those patients, they were very low risk of having emergency room visit or hospital admission in the following year. Thus, this group may not be benefited or may not be cost-effective to put them on daily or as needed inhaled steroids or a combination, because the cost might be too high. Then I tried looking for the cost-effective studies on these mild asthmatics, and there were only two or three available in the literature. This was one of them. This was done, I think, in Columbia. This study aimed to evaluate the cost-effectiveness of smart therapy compared with short-acting beta agonist in adolescents with mild asthma in Columbia. Total cost was calculated over the lifetime. All costs of each healthcare defined by the Murkoff model was extracted from the previous studies, and the data of relative risk on exacerbation rate was extracted from pooled analysis of Sigma 1 and 2 studies. They showed that the cost difference was about $4 per patient per year in favor of budesonide-formateral group. But if you look at the study in more detail, the cost of a combination medication in that study was $53, which is probably the cost in Columbia. In United States, that cost is $500. So imagine and put that numbers to the U.S. cost, and you can see the outcomes might be a little different. Now we have about 27 million asthmatics with asthma in United States alone. Worldwide, they are about 270 millions. If you look at mild asthma, intermediate asthma is present in about 50% of that population, and another 29% is mild persistence. So in total, you have about 20 million peoples with mild asthma in United States alone, of which at least 13 millions are intermediate asthmatics. The estimated economical cost of asthma in United States is about 60 million, sorry, 60 billion. And if you look at the annual per person medical cost of asthma care, it is about 3,200 per patient per year. And out of it, more than 50% is already being spent on the medications. And this is before the smart therapy or the guidelines are being implemented. So you can imagine how the cost will gonna increase. So at the end, I would say that cost of one inhaler is about 250. Cost of combination, such as Simpicort, is about $500 per inhaler. New indications means the patents will last for much longer time. The increased cost will persist for much longer time. And if you prescribe that to 30 million patients with intermediate asthma in US alone, you can imagine the increased economical burden on healthcare system, and apply that to the worldwide 130 million patients with intermediate asthma. And you can do the rest of the homework, and I will leave the decision up to you. Thank you very much for your time. And I'm sorry, I still support smart therapy, but in the right patients. Thank you.

Smart Therapy

asthma treatment

allergen immunotherapy

disease-modifying

immune system modification

allergic rhinitis

limitations

barriers

cost-effective

balanced discussion