I have nothing to disclose. The objective of this talk is primarily to share the expert panel report for on asthma management 2020 updates, and especially focusing on indoor allergy management and immunotherapy in allergic asthma. The most important part of the new guidelines is that if your patient is doing well on current therapy, please do not change anything. Having said that, let's briefly talk about the allergen mitigation. The recommendations on this topic is less noticeable. The expert panel recommend against indoor allergen mitigation as part of a routine asthma care, and it should be used only for the individuals who are, one, sensitized to the specific allergen, and also who also become symptomatic after there is an exposure. So just sensitization is not enough to try to clear out that allergen from the environment. The patient should also be symptomatic with the exposure, because many times sensitization may not be a bad thing to happen. There is something called tolerance to the allergens. It means that you are in an environment, you are sensitized to something, but your body is adapted to it in such a way it's tolerant, and if you remove that allergen, you may change the balance between a patient and the environment, and that in some cases may even have harmful effects. So being symptomatic is more important than just being sensitized. So there are two ways to do mitigation. One is the multi-component technique, and one is the single clearance technique. The recommendations are that when it's needed, the multi-component tailored intervention strategies should be used. For example, if you are worried about the dust mice and want to clear that antigen from the environment, the one single thing is not going to work. It should be a combination of a few things. For example, dust mite impermeable pillows and mattress covers, plus the damp dusting, plus HEPA vacuums. If they are worked together, then there's a much better chance for them to be successful than any of them alone. There's only one therapy which is recommended to be used alone if nothing else is available, and that is pest management, because cockroaches, we love them so much that we want to get rid of them, even if it works or not. So even for the pests like cockroaches or sometimes with rodent, a single mitigation therapy can also be applied, because studies have shown that that may have some impact. If you look at the type of the intervention and what is being recommended for, there are a number of different interventions. For example, there can be dust mite pesticides, which are, of course, recommended for the dust mites clearance. Then there is an air filtration system or air purifiers, which are being used primarily for animal dander and for the molds. Carpet removal, animal dander and the dust mites, cleaning, bleaches, and so on for the molds. HEPA vacuum cleaners are being used for animal dander and also for the molds, and pillows and mattress covers, of course, for the dust mites. Pest management, mostly for the cockroaches and occasionally for the dander from the rodents. Mold mitigation, of course, for the molds. And pet removal, usually for animal dander, though it rarely works or is very rarely recommended. Now, if you compare the single component strategy and multi-component strategies, given the evidence we have, looking at all these interventions, one at the same time, for the dust mites, it doesn't work. If you look for the impermeable pillows and mattresses, as a single therapy, it have no significance. But if you use it as a part of multiple-component strategy, there is a recommendation in favor of intervention. Similarly, carpet removals have shown no significance. Pet management is something which is recommended as a single-component strategy and also as a multi-component strategy, though the evidence of certainty is low. Air filtration systems alone are primarily of no use, and when they are used as a part of a multi-component, studies have also shown that they do not have any significant impact. On the other hand, if you look at the HEPA vacuum cleaners alone, they are not considered to be of significance, but there is evidence favoring their involvement with intervention, especially in the chair run. Carpet cleaning products, bleach and soap, not enough evidence. Mold mitigation only as when it's a part of the multi-component strategy, and pet removal, studies have not shown that it has any significant impact on improving the asthma or allergies by removing the pet from the environment. Now, briefly going over the immunotherapy, it is also a very touchy subject. Some people love the immunotherapy, others hate it, but the evidence is a little bit balanced. With the allergy immunotherapy, we know it reduces the IgE-mediated allergic responses associated with asthma. They can be of two types. One is subcutaneous and sublingual. Subcutaneous immunotherapy is recommended in ages five or above with mild to moderate allergic asthma, for whom the potential decrease in a long-term medication is important. It is not a part of a routine asthma management, but only in the selected ones. It should not be administered in individuals with severe asthma and individuals with persistent asthma, whose asthma is not under control at the time these injections are being given because studies have shown that it can cause harm. Now, if you look at the recommendation for the subcutaneous immunotherapy, it is recommended with a moderate certainty of evidence as an adjoint treatment to the standard pharmacotherapy in those individuals whose asthma is controlled. So this, as a replacement of medications or in lieu of medications, is not recommended. It's recommended as an adjunct to the therapy, whereas the expert panel recommend against the use of sublingual immunotherapy in asthma management. Now, when you quickly compare these two side-by-side with subcutaneous, it's recommended as the adjoint. Benefits are small improvements in symptoms, quality of life, reduction in long-term medications, may improve comorbid allergic conditions like allergic rhinitis, conjunctivitis, and so on. There is a risk of systemic reactions. It should only be used after optimizing control, should not be used in severe asthma, and it should be administered in clinical settings and not at home, whereas the sublingual therapy, it is not recommended in asthma because there is a limited number of allergens and most of them are FDA-approved only for allergic rhinoconjunctivitis. They may have certain benefits in individuals with allergic comorbidities, but the studies have shown very trivial improvement in asthma outcomes, and though it may reduce the quick relief and controller medications, but evidence is not enough to approve their use as a standard of care. Now, it should be administered in clinical settings where there is ability to monitor and treat reactions because there can be a lot of side effects. Patients should be observed for at least 30 minutes after injection. It should not be administered at home, and the panel recommended against the slit in asthma therapy, but it may benefit individuals with certain allergic comorbidities. The reason I'm mentioning it again and again is that there are certain strict recommendations and restrictions on use of these therapies. Now, the SCID or subcutaneous immunotherapy in allergic asthma can be considered when there is worsening symptoms with exposure and there's a confirmed sensitization to the same allergen. You can consider when it should, in fact, it should not be considered when the asthma is not optimally controlled, and the clinicians should not initiate, increase, or administer maintenance immunotherapy doses when the patient is having asthma symptoms. And why is it important? Because it is associated with harm. The side effects are highly variable. Local reactions can occur between 7% to 10% of the subcutaneous immunotherapy doses. Systemic reactions, it depends on the study you look at. There are some studies which says the systemic side effects is 0.1% of the injections. There are others which suggest it can be up to 10% to 12% of the injections, and it has been reported in about 80% of the practices. And it can be a combination of pruritus, urticaria, eczema, conjunctivitis, bronchospas, wheezing, dyspnea, abdominal pain, hypotension, and the list goes on. The incidence of anaphylactic reaction state, grade 4, occurs in about 1 in 160,000 injections in the studies between 2012 and 16. The recent studies have shown the incidence to be lower, and in all studies or the risks in some studies is as high as 1%. The incidence of fatal anaphylactic reaction ranges from 1 to 2 millions if you look at the studies between 1980 to 2000. But if you look at the recent studies, the incidence is between 1 to 9 million injections. And that is because it has decreased over time because of the more awareness and more closely monitoring these patients. So these are the recommendations, but the story is not done because there is a lot of rebuttal against these recommendations, at least from our allergic colleagues. I'll briefly mention two or three major points on this one. For example, a panel report says that there is a trivial benefit for the clinical critical outcomes that includes asthma exacerbations, asthma control, and quality of life. Whereas if you look at the rebuttals and the studies, it says that if you look at the systemic review and meta-analysis of SLIT for adults with asthma, SLIT ads on therapy was associated with significant importance in lower or upper airway scores, FEV1 and mean expiratory flow volumes, and the improved airway reactivity and inflammatory markers. And these counter-arguments are not for SCID, but for the SLIT sublingual immunotherapy because that immunotherapy's type of immunotherapy so far is not recommended for asthma use. The second recommendation on SLIT is that if you look at the expert panel report, it says that there are four studies that evaluated asthma control and validated tools and have found no consistent improvement following treatment. If you look at the both studies, which was Bley's study and the Wang study, that shows that asthma quality of life, especially asthma control questionnaire score and the asthma-related quality of life questionnaire scores, show significant improvement, but it was more in a subset of more severe patients. But the problem is for most severe patients, immunotherapy is not recommended to begin with. So that is a bit of controversy. The second and the last controversy is that expert panel did not find any SLIT, find that SLIT reduced asthma symptoms or improved asthma control or quality of life, whereas the, if you look at a rebuttal, it says that in their source document, it's clearly mentioned that SLIT improves asthma symptoms, improve quality of life, and decrease the need for the quick relief asthma medications and also for the long-term controllers such as inhaled corticosteroids. So there are some studies which have shown some improvement, but as far as the expert panel is considered, they do not think that those findings were significant enough to justify its use, given that if it's not, antigens are not FDA approved and the control is not systemic. So that's why it is not recommended, but it is very possible that in the next few years with the new recommendation, with more data, that things may change. So with this, I leave this topic. So thank you very much for attending. Thank you. All right. Good morning, everybody. Thank you for braving the cold weather and coming this morning. My name is Maryam Lewis, and today I'm going to talk to you about the updates on the use of fractional exhaled nitric oxide in asthma care as per the EP4 guidelines. So for disclosures, I am a member of the ABIM item writing task force for the sleep medicine initial certification exam, but this should not pose any conflict of interest for the purposes of this talk. All right. So why exhaled nitric oxide? As most of you remember, nitric oxide is a gas that can be measured in every exhaled breath that we take. Patients who suffer from the type 2 bronchial asthma may have increased levels of IgE, eosinophils, inflammatory cytokines like IL-4, 5, and 13 that can affect the inducible nitric oxide synthase enzyme in the epithelium, which helps to regulate nitric oxide production. As such, fractional exhaled nitric oxide may be a useful indicator of T2 bronchial or eosinophilic inflammation of the airway. So for those of you that are not familiar with Pheno, this is what the device may look like. It's a small handheld device, and it requires a coordinated expiratory maneuver into the mouthpiece. And after a few moments, the measurement will populate onto the screen. So if you have a patient who is unable to do a coordinated expiratory maneuver for whatever reason, the measurements may not be accurate. So that's something to keep in mind. So given the rapid expansion in our understanding of asthma care as well as technology, the expert panel assembled and reviewed the literature on the use of Pheno in terms of asthma care. They identified over 3,900 publications, of which 175 studies met their eligibility criteria. They came up with five questions and four recommendations on the use of Pheno when it comes to asthma care. So the expert panel concluded that overall, Pheno is safe for almost everyone. It must be done by an appropriately trained personnel with extensive experience. It cannot just be done on the fly. And it can be done in both a primary care setting or a specialty setting, which is great because it can help now expand asthma care into primary care settings. So the first question that the task force came up with was, what is the diagnostic accuracy of Pheno for making the diagnosis of asthma in individuals who are five years and older? So to answer that question, I just want to caveat that there is no definitive single test that currently exists to diagnose asthma, right? We all know that. And so as such, the diagnostic accuracy of Pheno to diagnose asthma is going to vary depending on the cutoff point. And I'll talk about that in a couple more slides. But overall, the task force found that Pheno measurements has a moderate diagnostic accuracy for asthma with a diagnostic odds ratio that range anywhere between 6 and 17 across different cutoff points. The sensitivity and the specificity also varied depending on the cutoff used of the Pheno measurements. More about that in a couple of slides. The task force also wanted to highlight that the diagnostic accuracy of Pheno measurements is higher in nonsmokers. So if you have a patient who is smoking, the Pheno measurement may not be an accurate reflection of the actual inflammatory component in their airway. Furthermore, and this I really, really want to emphasize, your Pheno measurement level must be interpreted in the right clinical context. And what do I mean by that? There are other comorbid diseases, as well as allergen sensitivities, such as allergic rhinitis and ATP, that in of themselves are associated with higher levels of Pheno, even in patients who do not suffer from asthma. So that's something to keep in mind. On the other hand, if you have a patient, as I mentioned, who smokes or is on steroids, your Pheno measurements may not be accurate. They may be actually lower than what they should be. And furthermore, Pheno testing has not been validated in children under the age of four. So some of you and most of you are probably already familiar with this table. That helps guide your interpretation of Pheno measurements to diagnose asthma in nonsmoking individuals who are not currently on corticosteroids. So Pheno measurements are reported in parts per billion. And if you have a patient whose levels are less than 25 in an adult or 20 in a younger age group, this can help you rule out the diagnosis of asthma in a steroid-naive patient. And so alternative diagnoses, such as the ones that are listed here, should be sought. On the other hand, if you have a patient whose levels are greater than 50 parts per billion or 35 in children 5 to 12, this is much more consistent with elevated T2 inflammation and supports your diagnosis of asthma. It can also help you identify those patients who may respond to inhaled corticosteroids. If you unfortunately have a patient whose levels are in between, which is the majority of my patients, then further workup is needed to help elucidate the etiology of the patient's symptoms. I want to caveat that you should never withhold your patient's inhaled corticosteroid in order to do a phenomeasurement. If your patient is on steroids and you want to do a phenomeasurement, go right ahead. But again, interpret it in that context that I told you about. So with that said, the task force's first recommendation is that in patients that are greater than five years, phenomeasurements can be used as an adjunct tool in the evaluation of asthma when the diagnosis is uncertain. Phenoresults should not, however, be used to diagnose asthma by itself. This is a conditional recommendation by the expert panel with a moderate certainty of evidence. The second question that the expert panel posed, and it's part A and B, is what is the clinical utility of phenomeasurements to select medication options for individuals five years and older, and what is the clinical utility of phenomeasurements to monitor the response to that therapy in that same age group? And so to address this question, the task force looked at three critical outcomes, namely exacerbations, asthma control, and quality of life metrics. They reported that phenotesting to monitor response to asthma was associated with a meaningful decrease in number of exacerbations, which is really important. On the other hand, phenomonitoring did not achieve minimally important differences for asthma control or quality of life indicators. And this is likely for several reasons. It could be that there's a low certainty of the asthma control test and other questionnaires that are used to assess control and quality of life. The strategies that are used to adjust therapy using phenotest results vary widely from study to study. The patient populations that are reported in the studies that were examined included patients with and without ATP, so it was a mixed population. And finally, there's really currently no evidence-based phenocut points that are available to the clinician or the provider to help guide the choice, monitoring, or adjusting therapy. So with that in mind, the expert panel said, well, who really should be getting phenotests? And they suggested that phenotesting may be useful to monitor asthmatic individuals who may have uncontrolled persistent asthma taking ICS or combination ICS-LABA, Montelukast, or Zolaire. It may be useful in patients whose symptoms indicate that they may require step-up therapy. It may be useful in patients who have ATP, particularly children. And this is important. Phenomonitoring is only useful if you have a patient who is willing to come in every two to three months to get assessed. So if you have a patient who's only going to come in once a year, it may not be very useful. Phenotesting, however, should not be used to assess adherence to treatment. That is not the role of pheno. And I want to emphasize the recommendations in the EPR-4 do not apply to individuals who are currently taking biological agents, with the exception of Zolaire. And this is because the data that was included in the EPR-4 only went up to 2018, so they did not include those patients. So based on that, the second recommendation by the expert panel is that individuals over the age of five with persistent allergic asthma and for whom there is uncertainty in choosing, monitoring, or adjusting anti-inflammatory therapy, phenomeasurements may be added as part of an ongoing asthma monitoring and management strategy. And this is a conditional recommendation with a low certainty of evidence. Moving on to the fourth question, which is, what is the clinical utility of phenomeasurements in monitoring disease activity and asthma outcomes in individuals who are over the age of five? And once again, the expert panel looked at four outcomes, sorry, three outcomes, namely exacerbations, asthma control, and quality of life. And as I mentioned earlier, they reported that amongst adults, phenol levels were weakly associated with asthma control, as measured by the asthma control test or asthma control questionnaire. But what was interesting is that this association is weaker amongst individuals who smoke, which is not surprising, as we mentioned before, who are pregnant, and who are taking ICS. The task force also found that there was inconclusive and weak evidence on the utility of pheno in predicting exacerbations. So if your phenol level is 75, it does not mean that you're going to get an exacerbation. They also found that phenol levels did not correlate with exacerbation severity. And it's not reproducible during an exacerbation. So keep that in mind when you have patients who are coming in. So the third recommendation that the expert panel recommended is that phenotesting should not be used in isolation to assess asthma control, predict a future asthma exacerbation, or assess the severity of the exacerbation. As such, phenotesting is not a substitute for your standard measures. And once again, should only be used as part of an ongoing monitoring and management strategy. Strong recommendation, low certainty of evidence. So the final question that the task force addressed was what in children age 0 to 4 with recurrent wheezing, how accurate is phenotesting in predicting the future development of asthma once these children are over the age of five? And I want to caveat, it's really hard to get these children to do a coordinated expiratory maneuver. So take that with a grain of salt. And it's not surprising, there were only 10 studies that were identified and included in the guideline, none of which were random control studies. And unfortunately, the results were very variable. There were four studies that were examined, whether elevated phenol levels in children predicted future asthma exacerbations. And those had mixed results. One study that the task force looked at showed that phenol levels had a positive predictive value of 58% and a negative predictive value of 78%, which is very similar to the classic asthma predictive index without the use of phenol. So it didn't really add much to the current knowledge base. And so therefore, although phenol levels appear to reflect eosinophilic bronchial inflammation early in life, the current evidence is insufficient to draw any firm conclusions. And so the final recommendation by the expert panel is that in children age 0 to 4 with recurrent episodes of wheezing, phenomeasurements do not reliably predict the future development of asthma and should not be used to predict the future development of asthma. This is a strong recommendation with a low certainty of evidence. So on a final note, I've got two more slides. The expert panel was very concerned about access and equity, particularly in the United States where there may be some restrictions to phenol due to insurance coverage. And so they were concerned that there may be disparities of asthma outcomes if not everybody has equal access to this technology. And they recommended a cost-effective analysis to be conducted in the United States addressing this particular potential disparity. So in summary, although the EPR did add quite a bit to our knowledge on the use of phenol in asthma care, there are clearly gaps, and the potential value for phenol in asthma care is still quite high. And so the expert panel actually came up with future research opportunities and questions that needed to be addressed. There's 14 of them. I could not include all of that on the slide. But just be aware that there's a lot more that will be coming in the future. And with that, I thank you for your time. My name is Norman Chowdhury. I'm in Virginia Commonwealth University in Richmond, Virginia. Thanks for attending. I'm professor of medicine there. Topic assigned to me today with this group today would be update on LAMA therapy in asthma. So my hope would be by the end of this talk, I can make convincing evidence for something of use of LAMA therapy, whether you are on the side of using it or on the side of against it. Let's review some evidence. I have nothing to disclose in relevance to this talk. The questions that I was trying to make this talk and I wanted to address with the audience today was when do we pick up LAMA? Who are the good candidates for LAMA therapy in asthma? What could be the mechanism of action in asthma? Could it be improvement in inflammation? Could it be improvement in the cholinergic tone? And how can we predict who will respond to LAMA therapy in asthma? Can we pick up patients? So let's touch base about the TH2 type inflammation asthma. So these are the patients who have eosinophil count more than 150. Their IgE elevation could be seen as well. Their pheno could be more than about 20 approximately. They have history of allergy, atopy, and usually they have early onset asthma. The people who have usually the non-TH2 inflammation asthma are usually seen at later age of onset. They have less allergy. They could have less atopy and they usually have less response to bronchodilators or oral corticosteroids. So touching base on the GINA 2020 guidelines. So as we all know by now that if you have less than two attacks of asthma per month, GINA 2020 recommended as use of low-dose inhaled corticosteroids along with long-acting beta agonist. And if you have more than two attacks in adults and adolescent, there was a daily use of low-dose steroids as well as you could have the option of as-needed or long-acting steroids or low-dose steroid as well as with formotrol. And if you have daily symptoms as well as nocturnal awakening, you could use LABA on top of using a low-dose steroid. And if you have low lung function, so the top three, step one, two, three, have normal lung function. And when your lung function declines and you have nocturnal awakening as well as more frequent symptoms, you could consider using a LABA with medium-dose steroids. And as you escalate it further, you could go to high-dose steroid with phenotypic assessment and going to anti-IL-5 therapy or IL-4 or other biologics. And I'm not a pediatric pulmonologist, but there were some differences there in the peds and the adult. And as we can see, the step one, there was less use of controller. There was also, I think that was the main thing. And also in the step three, you could also use medium-dose steroids as compared to the adults. So these are some of the ERS-ATS-2020 guidelines. So what are our options here? So the first thing would be that for severe asthma. So you could use anti-IL-5 therapy, as we have seen people who continue to have severe frequent asthma attacks. You could also suggest to look at the eosinophil count in consideration of your anti-IL-5 therapy for patients who have severe uncontrolled asthma. You could also use anti-IgE therapy. We frequently call it Zolair in US. And also for step four in this question, they address that to consider LAMA therapy. So people who continue to have symptoms of Gena-4, Gena-5, or NAEPP-5, the recommendation was to consider LAMA therapy. And then people also suggested to consider using trial of macrolide if you continue to add on and continue to have symptoms despite use of biologics and possible LAMA therapy. And then moving on to consider further biologic if you have eosinophil-independent asthma to consider dupilumab as one of the therapy as a step six in questions of these guidelines. So just to reemphasize in the guidelines, for children, adolescents, and adults with severe asthma who are uncontrolled despite Gena-4, Gena-5, recommendation was to consider using LAMA therapy. So how can LAMA help in severe asthma? And it is thought that it can improve symptom control in Gena-4, Gena-5 patients. It may improve FEV1 and increase time to first exacerbation. Side effects are thought to be similar to placebo and there is a concern that maybe LAMA would help better in people who have fixed or baseline airflow obstruction as compared to people who don't have that obstruction or have normal PFTs. Let's look at some of the studies here. So in this study, authors were looking at the effect of LAMA therapy in the first three hours and then going up for the next up to 24 hours of bronchodilation in people who had severe uncontrolled asthma. So there were two different doses of teiotropium were compared. In the red, it is the teiotropium R10. In the five microgram dose was the R5, the blue curve. And as we can see, both of those red and blue lines are above the placebo effect and there was sustained bronchodilatation that was seen in people who were given LAMA from three hours until 24 hours. These were the people who were already on a LABA therapy and inhaled corticosteroid therapy. In this study, authors were looking it up again, comparing inhaled corticosteroid as well as looking at the LABA plus LAMA and looking up the effect of teiotropium. And this study similarly shows not only that there was improvement in FE1 and sustained bronchodilation, there was also reduction in exacerbations that were seen in people who were given as a LAMA add-on in the frequency of exacerbations. This study, now the next question came up, can you do this LAMA therapy independent of the LABA therapy? So can you do just LAMA alone with steroid and do you really need LABA? So these authors were trying to address this in this study and people were allowed to take like Montelukast or some other biologic therapy, but they were not allowed to do the LABA therapy in this. So there was some improvement seen, but there was not really statistically significant response to that met the primary and secondary endpoints. They did notice improvement in the FE1, but there was some role of LABA that LAMA alone with steroid together could not just maintain and sustain. In this study, authors were again trying to address the same question about the doses of glycopyronium and looking it up, the probably escalating doses of LAMA to see will that have an effect on the bronchodilatation as well as the FE1 improvement, as well as looking up the same question of do you need steroids or independent of the steroids. So in the first side on the left side, these people were all subjects who were not on steroids and then on the right side, there were people who were on steroids. So again, the study did show that the addition of steroid does have an impact when you add that to people who are taking LAMA and LABA as compared to just without steroids. So there is some role of steroids and definitely as we all know in asthma, which LAMA cannot fulfill. Looking at this study, people were taking the same question about using humiclinidinium for the monotherapy without steroid and even though they did notice some effect of improvement in the FE1, a very modest increase, they did not notice statistical significance of improvement in the FE1 or the combined effect that can be seen with steroid and the LABA therapy. Now in this one, again, people are trying to address can you do fluticasone furorate with the valentrol or can you use ICS with LAMA? And the slide is kind of busy and small but the bottom line from this slide was that if you're going to use LAMA with steroid, there's benefit as compared to using LABA with ICS. So people, especially in people who have fixed airway obstruction. So people who were taking LAMA-ICS, fixed airway obstruction, did better as compared to people who had LABA-ICS without fixed airway obstruction. That was the message of this. So that brings us to the point, we have looked at LABA-ICS and LAMA-ICS and different people were trying to address in this study what are the predictors of response to LAMA? And they were interested in looking at the gender, looking at the BMI, looking at the eosinophil count, IgE level, and unfortunately, none of those were predictors of LAMA therapy. So still, the ball is out in the court to see who are the patients that we will pick up. They did notice people who had a bronchodilator response who were taking albuterol were the most successful individuals who would have a response to LAMA therapy. But those are majority of our patients sometime that we see in practice who have response to bronchodilator. The other thing that they did notice is that people who had cholinergic response actually did better with LAMA therapy. And how did they measure the cholinergic response? They were looking at the baseline heart rate. People who were less than 60, they responded better than people who had a higher heart rate. Similar study looking at the wide range of factors to response to LAMA. And in this study, they also looked up variety of factors including eosinophil counts, gender, race, ethnicity, et cetera, and none of those were predictors of LAMA response. So really, the same point is bronchodilator response, albuterol response, better response, and better chance to have a LAMA success. In this study, there were adolescents between 6 to 11-year-olds who had severe persistent asthma on high-dose steroids with more than one controller or one controller. The study did show that people did improve statistically significant from 250 mLs to about 400 mL in your FE1 as a primary endpoint. Also, there was a significant person increase, about 6.3% when these adolescents were given LAMA as well as to ICS and LAMA therapy underlying with severe uncontrolled asthma. More recently, this topic was touched again as a triple versus dual inhaler therapy among children between age 6 to 18 years and moderate to severe asthma. Triple therapy was compared and was significantly associated with fewer severe asthma exacerbation and modest improvements in asthma control without difference in quality of life or mortality. So people who are not in favor of using LAMA take this study and consider this that for a modest improvement in your FE1 or modest improvement in your severity of exacerbations, we have better drugs than LAMA because there was no change in quality of life. So this is counterintuitive. There's no difference in mortality. There's no difference in improvement in quality of life. But you're giving LAMA to improve exacerbations. So it doesn't really connect. But I don't know if that's what the study is showing. And people who are not in favor, they say there's no improvement in quality of life. So that's not going to make a difference whether you're going to use LAMA in people who have already been on LABA-ICS. And then finally, I think in this study also, authors are trying to address the ICS-LABA treatment is not inferior to ICS plus LABA plus LAMA. Now, these are the people who have asthma, COPD, overlap syndrome. So interestingly, these are the people who respond better when they have fixed airway obstruction. So they have less response to bronchodilator. And they also have some overlap syndrome picture. And I think the, I just wanted to highlight this, that reviewers have looked it up, like who could be better responders to LAMA therapy. And this observational study shows that when LAMA is prescribed, it is often without concurrent ICS. So that's the point that I would like to highlight today. LAMA without ICS and asthma should not be given. And there is an increased risk of exacerbations when not used concurrently with ICS. This emphasizes the importance that LAMA should never be prescribed without ICS. So take-home message that I would like to put together. So for type 2 people who have asthma, consider using steroids for three to six months. And look at the phenotypic expression of asthma. Try to address if they have ABPA. Look for nasal polyposis, sinusitis, ATOP. And then look at the biologic therapy. If you're going down the pathway of type 2 inflammation without the evidence of type 2 inflammation, no eosinophils, no IgE elevation, look at the technique. Look at the expoyers. Consider doing imaging. Then you would think about adding LAMA to ICS and LABA. Also, I would never use low-dose oral corticosteroids. If this is short-term, you could consider it. And you can stop ineffective therapy and consider thermoplasty. So I think we looked up to people who are going to be good responders to LAMA, people who could look at the predictors of LAMA therapy. Also, look at the mechanism of action of people who could have bronchodilation as well as cholinergic tone and people that can benefit from possible people who could have the, I think, the last slide, the inhaled corticosteroid should be used concurrently with LAMA therapy. Thank you very much. I'm Dan Ouellette. I'm at Henry Ford Hospital in Detroit. Thank you for inviting me to help out with this session today. We're going to talk about smart therapy. And I'm going to tell you a little bit about what that is today. Here are my disclosures. I have several research grants that involve COPD and sarcoidosis. One other potential form of bias is I was on the EP4 panel. So I'm going to talk about the EPS. I was on the EP4 panel. So some of the things that you'll hear about relate to my work with that group. There is one important disclosure that I need to talk about with you before today. And that is that smart therapy involves the use or strategies for inhaler use for which these medicines haven't been approved by the FDA. Now, the FDA has approved the medicines we're going to talk about. But the FDA approves indications and dosing regimens too. And smart therapy has not been approved by the FDA in terms of the dosing regimens. The interesting thing to me is that the EP4 guideline was based on an evidence review that was conducted by the NIH. And the EP4 was sponsored by the NIH in the United States. So the guideline that is the basis for what we're going to be talking about, that plus GINA, is sponsored by the federal government. And another branch of the federal government, the FDA, hasn't approved the medicines for dosing in this way. This is not an esoteric point. This is important in your practice. And I'm going to talk about that a little bit later today. So today, we're going to talk about revised asthma guidelines. I'm going to focus on GINA and EP4. We're going to learn about single maintenance and relief therapy, which is smart therapy. And we're going to talk about future directions in asthma therapy. I don't think that we have an audience response system. But I do have embedded questions for pedagogic purposes. So I'm going to go through those. And when I show you the question, you can think about what you might answer. Because I think that the points that I'm going to make with the questions are things that are important to talk about. So imagine that you're taking care of a 20-year-old female college student who's home for the summer. And she had a history of asthma. She used her albuterol maybe once or twice a month, not very often. But now she has frequent symptoms. She's using her albuterol inhaler frequently. She has some nocturnal symptoms. She has a number of triggers. You do a spirometry in your office, and it's normal. She had a history of a positive bronchoprovocation challenge in the past, so you're sure that she's got asthma. And right now, she has a moderate obstructive defect, but she has a bronchodilator response. So she has persistent asthma. And what would you do next which you would think would be the best in accordance with GINA or NIH guidelines? Would you add an LTRA to the patient's regimen? Would you substitute a scheduled and as-needed low-dose ICS for motorol inhaler for the albuterol, supplement the patient's regimen with a moderate to high-dose scheduled ICS, or begin azithromycin three times a week in addition to the patient's albuterol regimen? What I would do, my choice would be number two. I would use scheduled and as-needed low-dose ICS for motorol, which is smart therapy. This is from the GINA guideline and showing step three for persistent asthma, that the current recommendation in step three would be a low-dose maintenance ICS for motorol inhaler, plus using that inhaler as a reliever. And that represents smart therapy. In our EP4 guideline, at a similar stage, we recommended for adults 12 or older to use smart therapy with a single inhaler with an ICS for motorol for treatment. And so that would be my best choice. In terms of adding the LTR, this is, in GINA, an alternate choice, as it is in the NIH guideline, so it wouldn't be the first choice, although it's not clearly wrong. It's something that sometimes one might do based on individual circumstances. The other question with moderate to high-dose ICS and a LABA would probably fall out, because both GINA and NIH, for persistent asthma, would recommend a low-dose at this stage. In GINA, track two on step three offers an alternate of a daily low-dose ICS and LABA. Step two in the NIH guidelines is a daily low-dose ICS, and step three is low-dose ICS plus for motorol. So the moderate to high-dose might not be the best choice at this point. And in terms of azithromycin, I hope all of you know about the MAZE trial, which is in patients with very severe asthma, adding azithromycin to a regimen, which demonstrates improvement in control and reduction in exacerbation rates. However, our patient that we've talked about in the stem of this question didn't really have severe asthma that would fit the need for this therapy, so I don't think that that would be the best choice for her at this time. This is from EP4, and this goes over the guideline recommendations. And what we recommended was that daily ICS, daily and as-needed ICS and for motorol in step three and four was compared with either daily ICS and as-needed short-acting beta agonist, daily same-dose ICS and LABA plus a SABA for relief, or daily higher-dose ICS, LABA, and as-needed SABA. And three recommendations, or two really, 12 and 13, recommended with fairly good evidence that we use smart therapy as opposed to these other types of interventions. So I would encourage you in this group of patients with persistent asthma to consider for motorol and an ICS as smart therapy, single maintenance and reliever therapy. One of the reasons to choose for motorol, which I'm going to talk about a little bit more later, is that for motorol has a relatively rapid onset of action compared to other LABAs. And for that reason, for motorol is preferred to these other choices. And so I would encourage you to think about that. So does smart therapy change asthma outcomes? That's actually what we're interested in, right? We want to know if this is going to make our patients better. So here's a completely unfair and tricky question. But I put it here not because it's a board review thing, but because I wanted to emphasize certain points. And I think going through the trickiness and unfairness will bring out a couple of points that are important. So which of the following statements is true about asthma outcomes in smart therapy when you're stepping up therapy from genus stage two? Compared to budesonide for motorol plus a short-acting beta agonist, does budesonide for motorol as a maintenance and relief therapy, does not significantly reduce severe exacerbations in patients using less than one reliever dose per day. Is that true? Compared to budesonide for motorol plus a SABA, budesonide for motorol as maintenance and release does not significantly change FEV1 in patients using less than one reliever dose per day. Compared to budesonide for motorol plus a short-acting agent, smart therapy does not significantly reduce time to first exacerbation. Is that true? Compared to fluticasone salmeterol plus salbutamol, budesonide for motorol does not significantly reduce time to first exacerbation. For me, the best answer is the first, the most likely wrong, and I'm gonna show you why. This is from Jenkin's study, which rated, looked at the baseline reliever use and looked at mean severe exacerbations per year. And in the group that was using relievers less than once per day, the difference between smart therapy and fixed-dose budesonide was not statistically significant, though there was a trend to favor smart therapy, which is why it's not a fair question. So the wrong answer is that one. But in most groups, there's evidence that smart therapy improves or reduces exacerbations. Compared to smart budesonide for motorol plus a SABA, smart therapy does, in fact, significantly change FEV1 for those who are using even less than one reliever dose a day. And the three categories, less than one, one to two, and greater than two, are listed here for you. In terms of leading to reduction in reliever use, smart therapy did better. And in terms of time to exacerbation compared to a ICS LAVA plus a short-acting agent, in fact, time to exacerbation was improved, as it was if you used a different ICS LAVA combination. So smart therapy does significantly improve outcomes in asthma, and is something that we should be considered. As I mentioned before, for motorol has a relatively quick onset of action compared to the other LAVAs, and that's why you can't really substitute another ICS LAVA combination for the budesonide for motorol combination. Challenges with smart therapy are these, and I find this daily in my practice. First of all, there's a cost issue because they need to get this medication. There's formulary availability problems. I have patients where I go to prescribe a for motorol ICS inhaler, and the formulary says, no, you can't do that. This other one is our preferred inhaler, and it's got a different LAVA, so that's a problem. The FDA indication is a problem, because if you wrote a prescription for smart therapy, the insurance pharmacist might not know what to do with it. So to me, that's a challenge, and I think we need to overcome that disconnect. I think that what you often have to do is write a standard prescription for the agent, and then have an informed discussion with your patient on how to use it, and so that means you've got to have the right patient. They've got to understand what you're trying to do, and they've got to be engaged in this process, and that, for me, is sometimes challenging. I work in Detroit in an urban center, and sometimes my patients are challenged in understanding all of these things, and I find that a big barrier. So patient education and education of providers and of the rest of the healthcare industry is gonna be important. Can we get even smarter than we are now? So let's talk about a patient who has, is a new patient who is a 24-year-old man with cough. He's a nonsmoker. He works in Michigan, so in the summer, he's doing landscaping, and in the winter, he does snow removal. That's what guys do in Michigan. His triggers are cold air and aeroallergen, so no matter what the season, he's got issues. He's got normal spirometry and normal X-ray. His methacholine challenge is positive. He's got asthma, but it seems to be pretty mild, so what do you do? Do you just give him an albuterol inhaler and send him on his way? Do you give him a smart therapy combination ICS Laba? Do you give him a short-acting beta agonist ICS combination inhaler, or do you give him fluticasone and Volanterol? So I think this is an interesting question. I didn't even put a right answer here. My best answer for today, October 22 in America, is to use the budesonide-fumodorol combination inhaler, but the other choices have some traction, and I'll tell you why. For one thing, in EP4, the initial step one is a short-acting beta agonist is the initial treatment. So you're not wrong in doing that. Gina doesn't say that, but EP4 does. As my colleague said, our EP4 guideline was based on a literature review that was completed in 2018. We did the guideline in 2020. It's 2022 now, so Gina's a little more recent, but Saba is not totally wrong as far as an answer. In terms of Gina or what I think should, where we're at in EP4, the idea is to use either an ICS-fumodorol inhaler as needed, or to take a Saba, or take an ICS whenever you use a short-acting beta agonist. That's a reasonable thing to do. In terms of mild asthma, what we know is that smart therapy works. This is a study which looks at different treatment groups, including ICS, smart therapy, and albuterol, and shows that the smart therapy group does better in terms of reducing exacerbations and in terms of helping with nitric oxide. So I think that this combination therapy is a better choice. So I think that's what I would do. This is a complex study that came out in 2007. They actually had four groups. They had an as-needed combination group, which was beclomethasone and albuterol in a single inhaler, as-needed albuterol alone, regular beclomethasone, which was beclomethasone plus albuterol as needed, and regular combination, which was beclomethasone and albuterol in a single inhaler, twice daily, plus albuterol as needed. The group that got as-needed combination therapy did better than the rest of the group, a Saba and an ICS in a single inhaler. That was choice three. Well, guess what? We don't have this inhaler in America. So even though this looks like a pretty nice choice, we don't have it. So you could do this. You could give them both those agents and tell them to take both, but you don't have this single inhaler, which we may in the future. So that's something to think about. So there's no beclomethasone-Saba inhaler available in the U.S. to use. Interesting question number four, what we're finding out, what we realize is that there are certain ultra-LABAs, ultra-long-acting LABAs that actually have a relatively short onset of action. So are these good choices for the future? Should we explore that? That would be an interesting thing to think about. So what are we going to do in the future? We gotta figure out how to use smart therapy because I think it's the best therapy for our patients. We have to look forward to a Saba ICS inhaler in America. The role of LAMA in smart therapies would be an interesting idea that we need to incorporate. And what about ultra-LABAs and smart strategies? Thank you very much for coming and visiting with us today.

SMART

asthma management

inhaled corticosteroid

maintenance medication

reliever medication

persistent asthma

Formoterol

LABA

exacerbations