Gerry Lee, MD (Host): [00:00:00] Asthma exacerbations continue to affect over 40 percent of asthma patients each year, which not only disrupts their quality of life but can lead to permanent loss of lung function. The goal of this podcast series, Shifting the Asthma Rescue Paradigm, is to review why an anti inflammatory reliever has become the standard of care in asthma management and can also to provide tips on how to implement this therapy in your practice.

Hello everyone, my name is Gerry Lee. I'm an Associate Professor at Emory University, and the host of this second part in a three part mini series entitled Shifting the Asthma Rescue Paradigm, A Call to Action, from the American College of Allergy, Asthma, and Immunology. In this episode, we will discuss implementation strategies of an anti inflammatory reliever in mild asthma patients.

And in [00:01:00] the next episode, we'll just discuss the maintenance and reliever therapy in more moderate to severe asthma patients. I'm excited today to be joined by two experts in the field of asthma. Our first expert is Dr. Leonard Bacharier. He is the Janie Robinson and John Moore Lee Chair in Pediatrics at Vanderbilt University Medical Center.

He is a Professor of Pediatrics and Allergy, Immunology, Pulmonary Medicine, and he is the Scientific Director of the Center for Clinical and Translational Research at Vanderbilt. Dr. Bacharier's career has been focused on clinical research, to help understand and improve the care of children with asthma and his clinical translational research efforts are directed at the pathogenesis of asthma in early life and approaches to asthma management throughout childhood, including multi center, federally funded clinical trials in asthma. Len, thank you so much for joining the podcast.

Leonard B. Bacharier, MD, FACAAI: Thanks, Gerry. [00:02:00] Great to be here.

Host: Our second expert is Dr. William Anderson. He is an Associate Professor of Pediatrics at Children's Hospital Colorado and the University of Colorado School of Medicine. He is the Medical Director for the Allergy and Immunology Section. Dr. Anderson's clinical and scholarly interests include the management of difficult to treat and severe asthma, pediatric to adult care transition and technology and medicine, including electronic medication monitoring.

He directs the Multidisciplinary Asthma Clinic and their Asthma Biologics Program. Dr. Anderson also leads hospital wide pediatric to adult transition initiatives for Children's Hospital Colorado as the co-director of the Improving Pediatric to Adult Care Transition, or IMPACT, Program. Bill, welcome again to the podcast.

William C. Anderson III, MD, FACAAI: Thanks, Gerry. Happy to be back.

Host: Okay, well, let's get started again. In the last episode, we reviewed the rationale [00:03:00] for an anti inflammatory reliever. Just to catch us up again, Len, could you give a quick definition of what a AIR or anti inflammatory reliever is?

Leonard B. Bacharier, MD, FACAAI: Sure, Gerry. So historically in asthma, we have provided rapid onset bronchodilators in the form of short acting beta agonists, most typically albuterol. And these are what we have long considered our conventional relievers. They are pure bronchodilators with no anti inflammatory properties. As emerging research has really taught us, inflammation is the cornerstone to asthma.

It is the driving factor of exacerbations, and people have long wanted to improve our ability to prevent exacerbations. And the concept of AIR is sort of natural outgrowth of that. And it's really the concept that any time rescue is required, instead of just providing a simple [00:04:00] bronchodilator, we actually provide an additional bolus of inhaled corticosteroid to provide inflammation at times where clearly inflammation is present because symptoms are present.

This can be done with rapid onset bronchodilators such as albuterol or formoterol. These have different durations of action but are comparable in their acute onset and we are able to deliver this as either a single inhaler strategy or in multiple inhalers depending on the clinical situation and availability.

Host: So we're going to focus today's episode on the implementation of AIR on a typical patient. So let me start with a typical case, just a grounded discussion. Let's say you see a 23 year old college student with a history of seasonal allergic rhinitis and asthma. She really only mentions her asthma during her visit because you asked her.

She only uses her albuterol inhaler less than twice a month. And, you know, she had this one urgent care visit last year requiring [00:05:00] prednisone, but that was due to influenza and, you know, that's a part of asthma. You do spirometry today and she doesn't have any evidence of obstruction. So, Bill, when you see a patient like this, what does the asthma guideline tell us on how to approach this.

William C. Anderson III, MD, FACAAI: I would classify, Gerry, this patient as having intermittent asthma, given, the relative paucity of her symptoms and the lack of recurrent exacerbations. So, when we think about the guidelines, we have two options on the table. One is our NHLBI guidelines, and the other is our Global Initiative for Asthma, or GINA, guidelines.

So, our NHLBI guidelines were last updated in 2020, and at that time, they said that the preferred option for this patient would be as needed SABA. I would say that is 2020, that's several years ago now, and we have greater evidence, and as we discussed in the first podcast, there is great evidence for why [00:06:00] we should be using an anti inflammatory in addition to a reliever therapy.

 So, in this case, I defer to GINA, which says that the preferred treatment option would be to take a low dose ICS formoterol as needed. An alternative therapy for that could be to use ICS with a SABA, and that could either be in a combined inhaler, if available, or as two individual inhalers.

Host: So,really the updated guidelines, even since 2020, has suggested that we should use an anti inflammatory reliever. What was the rationale or research cited by GINA to change this guideline?

Leonard B. Bacharier, MD, FACAAI: So this is really a paradigm shift in our thinking toward asthma care and it was based on a very substantial body of evidence. The first bit of evidence that's essential to recall is that SABA alone has never been demonstrated to be an [00:07:00] effective approach in preventing exacerbations. it is a reactive therapy and there are no data that show that giving SABA proactively, is in any way preventive of exacerbations.

Second point is that there's substantial evidence that unopposed regular SABA use actually augments and increases airway hyper responsiveness and decreases the bronchoprotective effects of short acting beta agonists. So there's actually a true detriment to airway physiology with unopposed SABA use.

There were two very large trials reported in the last several years that really studied this carefully. They were called SIGMA 1 and SIGMA 2 The SIGMA 1 trial enrolled over 3,800 patients with mild asthma, and it showed that the use of as needed ICS formoterol, without any background therapy at all, provided better symptom control than [00:08:00] patients who receive just as needed SABA.

But if you compare that to patients who receive daily ICS, it wasn't quite as good at day to day symptom control. However, if you look at the more extreme example of asthma activity, that is exacerbation rates; they were actually similar between the as needed ICS formoterol group and the group that received daily inhaled corticosteroids, and both of these were significantly lower than as needed SABA.

And finally, that ICS exposure was actually lowest in the group that received as needed ICS formoterol. This was accompanied by a trial named SIGMA 2, had a little over 4,200 patients, and this one clearly demonstrated that using an AIR approach, that is ICS formoterol, was superior to using SABA alone for rescue, and was not inferior to daily [00:09:00] ICS on the risk of severe exacerbations in patients with mild asthma. Furthermore, the group that used ICS formoterol for rescue alone used one quarter the amount of ICS. There have also been several studies that have studied the examination of PRN ICS SABA and have also shown that there are lower rates of exacerbation compared to SABA alone.

 The literature is entirely consistent that the addition of an inhaled corticosteroid to a rescue bronchodilator reduces the risk of exacerbation at least as well as daily low dose inhaled corticosteroid and potentially better.

Host: So, you know, Len, you've quoted two studies with thousands of patients that has a substantial evidence, just a substitution, of a rescue inhaler that contains inhaled steroid can really move the needle on exacerbations. But we're finding that that's not often implemented [00:10:00] in practice and, Bill, what do you think are the barriers to this implementation if we just have such substantial evidence?

William C. Anderson III, MD, FACAAI: I think one substantial barrier is just a lack of knowledge about this evidence. Oftentimes, providers are hesitant to do things that aren't outlined specifically in the guidelines, and most providers I feel are very familiar with NHLBI, and more so now they're coming around to GINA, and so as we talk about this, as it gets incorporated into guidelines, I think we're going to start seeing some practice changes.

 Beyond the providers, also this is a bit of a departure for patients who for years have been told, well, this medicine is a controller, this is a rescue. Don't take this one on demand, do this one every day. So the idea that maybe they're getting some steroid just on demand or at the same time as a rescue, is a new concept for them.

And so that takes some paradigm change in their way they approach it. And then finally, we obviously, I have to think about [00:11:00] insurance coverage and access to these drugs, which can vary between plans in different parts of the country and around the world. So there's both the knowledge aspects of it, the approaches, and the logistical aspects of it.

Host: Yes, I think we've all encountered those barriers. I've definitely had pharmacists. you know, ask me and you know, I'm obviously going to send them the guidance as well. So I absolutely relate to everything you've said. So, you know, we started with a more mild patient, but let's talk about someone with potentially more severe asthma. Let's say you have the patient come back and now they're having twice weekly symptoms. They meet criteria for step 2 asthma therapy. Len, how does the guidelines approach step 2 therapy versus the intermittent patient?

Leonard B. Bacharier, MD, FACAAI: So, as symptom frequency increases or exacerbation risk increases, our two guidelines actually are not in sync with one another at this point. If you view the GINA 2024 report, the [00:12:00] preferred approach for somebody like this would be a PRN, as needed, ICS formoterol, as a AIR strategy. But an alternative could be a daily low dose ICS with as needed SABA added, or the strategy of using an ICS whenever a SABA is taken as a two inhaler strategy, and that's supported by the data we discussed.

The NAEPP update in 2020 does not include this as needed ICS formoterol option as unopposed therapy, and this is likely due to the fact of the timing that when the 2020 update was developed, these SIGMA trials were not yet fully available and therefore could not be considered in their determination.

And thus, they recommend daily low dose ICS as the recommended approach, but do acknowledge that the ICS strategy, whenever a SABA is taken, is indeed, an alternative that can be considered, and that is the AIR [00:13:00] approach.

Host: Len's laid out three different approaches from the guidelines whether that's being ICS formoterol, ICS SABA, or even again the older guidelines with daily ICS as needed SABA. So Bill navigating those options, what are sort of your approach in this step two therapy and the implementation of the guidelines?

William C. Anderson III, MD, FACAAI: As Len laid out very well at the start of this, we have great evidence for this ICS formoterol on demand approach, or ICS SABA on demand approach versus a daily ICS, with the idea being that the daily ICS, you're also getting a greater exposure to a steroid. So if all things are being equal, my approach would be to use the ICS formoterol, on demand in this population as that is the preferred recommendations from the [00:14:00] guidelines.

If for different reasons that's not available, whether it is an insurance or an access issue or through shared decision making, that's something that the family, or the patient doesn't feel comfortable with; in this case, for patients 12 years and older, GINA would recommend the daily low dose ICS with the reliver being ICS SABA as Len has outlined, or just as needed SABA.

So, once again, we have a preferred approach, we have evidence for why that is the preferred approach, but, if that is not feasible, then we can kind of defer back to what we've maybe been a little bit more accustomed to in this situation, which is a daily controller therapy with on demand, with that on demand potentially including an AIR option.

Host: So Bill mentioned a lot of these guides also focus on 12 to above and so I think we should talk about younger patients. Len, is there a different approach for the implementation of an anti inflammatory reliever for 5 to [00:15:00] 11?

Leonard B. Bacharier, MD, FACAAI: So, we enter a bit of an evidence light zone as we get into the school age population, in that we're really limited, but do have a couple of well conducted randomized control trials called TREX and ASSIST, that both examined whether the use of separate inhalers, one containing inhaled corticosteroid and one containing SABA, and whenever SABA was needed, additional ICS was provided.

And these have been conducted in children as young as six years of age. And both studies found that this strategy was indeed superior to SABA alone in terms of risk of exacerbations. So consistent with the data in adolescents and adults, and also associated with lower overall inhaled corticosteroid exposure, which is a very favorable outcome in this age group.

Host: Bill, what about the under five population, do we have anything similar to the school age [00:16:00] children about the evidence for AIR?

William C. Anderson III, MD, FACAAI: Thinking about AIR specifically, we do not have robust evidence at this time to recommend this kind of approach. Hopefully in the future we will have that kind of evidence, but we're not there yet. So I want to be clear, that we're talking about this four and under, we're not thinking about AIR.

However, there is one approach that can be used as an on demand therapy in this younger zero to four age patient population who has exclusively viral induced symptoms. So if they're having any kind of symptoms outside of a viral induced exacerbation, for example, difficulty with exercise or day to day symptoms, we don't want to use this approach.

But in this approach, with this patients who have these viral induced, or illness induced exacerbations; you can start high dose inhaled steroid at the very first onset of illness. Um, the study that explo that explored this was the MIST trial, and they used one [00:17:00] milligram of budesonide twice daily at the very first onset of illness, and used it for seven days, and used it in conjunction with a reliever therapy, in this case, albuterol.

So, what I would say is that if you have a patient that wants to use this kind of approach, it's a great way to make sure that they're being treated during their exacerbations. It's also a great way to reduce their overall steroid exposure during it. As the study showed that it was comparable to being on a daily low dose inhaled corticosteroid in terms of time to first exacerbation, but the kids overall got significantly less inhaled steroid approach with using this on demand therapy.

Host: Bill, thank you for that summary, and Len as well. I think, you know, we're all challenged at the implementation of different groups or ages, but this is a very good starting point. So, that concludes part two of this three part series. In the next episode, we will talk about the more [00:18:00] moderate, severe patient and maintenance reliever therapy.

If you like what you're hearing, I'd like to hear other episodes on the Allergy Talk channel; please visit college.acaai.org/allergytalk. My name is Gerry Lee. I'm representing the American College of Allergy, Asthma and Immunology, and I hope you enjoy the rest of your day. Thanks for listening.