[00:00:00] Amy: Welcome everyone, to the new season of ATS Breathe. Easy. We're glad to be back after a short summer break. I'm one of your hosts Dr. Amy Attaway, and I am so excited to be here with, Dr. Njira Lugogo so just to give some background, Dr. Lugogo is a clinical professor of medicine and director of the University of Miss Michigan Asthma Program.
She will tell you she has a clear passion for asthma and for those who are watching the video, you would be able to see in the back of [00:01:00] her office. She has an asthma warrior. a picture on the back of her wall. So as you can see, a perfect person to talk to about our, our topic today, which is going to be about anti-inflammatory rescue therapy and asthma, and can't wait to kind of dive into this topic.
So thank you so much for, joining the podcast.
[00:01:23] Njira: Thank you for inviting me. I'm really excited to speak to you today.
[00:01:27] Amy: Oh, thank you. Can you start by maybe explaining what anti-inflammatory rescue therapy means for asthma and how this may differ from like maintenance therapies or smart therapy?
[00:01:41] Njira: Well, you know, so I think what we need to remember is that asthma is a disease of inflammation and bronchoconstriction.
And, you know, the premise for anti-inflammatory rescue therapy is that in the past we would really think about. As [00:02:00] being targeted, its smooth muscle constriction and relaxation, but if you really think about the pathophysiology of the disease, when you have acute symptoms, you likely have inflammation, and that inflammation is actually intricately tied to bronchoconstriction, and may in fact at times be driving.
Constrictive phenotype that patients have. And so in a way it never quite made sense to just give people rescue therapy that bronchodilate. And the description I give my patients is we are opening a clogged tube, so the airways inflamed. You have mucus production, hyper secretion, and there's also, a lot of airway edema, which you can visualize if you're looking at the airway of somebody who's acutely sick.
And so for asthma, now what we want to do is couple. Anti-inflammatory therapies with fast acting relievers, [00:03:00] targeting the two components of poor asthma control. When you have a person who's acutely unwell, wheezing and having broca constriction, they have inflammation, you need to treat both things at the same time.
And so air therapy really stands for anti-inflammatory therapy, coupled with a fast acting bronchodilator. Why do we use fast acting bronchodilator? That bronchodilator could be a short acting beta agonist, such as albuterol, or it could be. Long beta, but only in the form of formoterol. So FOMO is the only LABA that can be used anti-inflammatory rescue because of the rapid onset of action.
Now, air therapy spans the spectrum of the full GINA table. So if you are on the milder end, perhaps that's the only therapy you're on because you have intermittent symptoms. On the other hand, if you are on maintenance therapy, [00:04:00] which is something you're supposed to be taking every day on a chronic basis, you still have intermittent episodes of increased inflammation, driven by viral illness, environmental exposures, and so forth.
And during those intermittent episodes of forced symptom control, likely with inflammation and constriction, you need anti-inflammatory therapy. In that case, again, we shouldn't only bronchodilate, we should be giving anti-inflammatory. Fast acting reliever therapy that is, by the way, still called air therapy, so any fast acting anti-inflammatory reliever therapy across the GINA spectrum is called air therapy.
On the other hand, maintenance and reliever therapy is really in that middle group there, the Gina threes and fours primarily. These are people who can take a FOMO containing inhaler for maintenance. Usually twice a day and then [00:05:00] ramp up that treatment if they have acute symptoms. So it's the, it's the maintenance therapy you're using, but you then are able to increase your containing inhaler up to 12 times, 12 puffs a day in adults and eight puffs a day in, um.
Children over six and adolescents to get, I mean, in children over six to get you that anti-inflammatory therapy. And so children over six, up to 11 is eight puffs, 12 and older plus adults. You are talking about taking up to 12 puffs a day. It used to be called smart because it was supposed to be single maintenance and reliever, meaning you're using that singular inhaler for both.
But now the new, um. Word that's used is just maintenance and reliever therapy or March. I hope that explains it. It's a little bit confusing, but if you really think about the disease, you just have to remember acute symptoms. You have constriction and [00:06:00] inflammation. You have to target both at the same time.
And what you call that, you know, is not quite as important as the principle behind why we've changed what we do.
[00:06:13] Amy: So, no, I think that makes a ton of sense. and that you have to like, think, think inflammation and bronchodilate, right? Like you have to think we're treating both at the same time, you know, even when a patient is having, needing rescue therapy.
[00:06:29] Njira: Exactly.
[00:06:29] Amy: so I guess one of the things that's. Bit taking the other side of things. Mm-hmm. Because I think that especially in mild patients, you still see maybe short acting, bronchodilator or therapy as being the only treatment, right? Mm-hmm. for these patients. Mm-hmm. what do you see kind of on the flip side of that?
Like what happens to these patients that are just using, a short acting beta agonist without an anti-inflammatory component? [00:07:00]
[00:07:01] Njira: Well, I mean, there's a lot of data on this now and I think, you know, short acting beta agonists were, came onto the market many years ago, you know, in the fifties. And, you know, patients inherently want symptom relief.
So our previous treatment paradigm, which was convincing a person with milder disease, to. Take medication every single day when they don't perceive any symptoms. Although now we have to actually start educating our patients and ourselves by measuring inflammation, using nitric oxide and blood eosinophils to figure out who's at risk.
Because not everyone is not at risk. Just, you know, I always tell patients, just 'cause you have no symptoms doesn't mean you have no risk. But that being said, and put aside inherently as a patient. You don't want to take medicine every [00:08:00] day when your perception is that you are quote, fine, you don't feel badly.
You want to be able to take medication on demand though when you feel symptoms and you want immediate relief. And I think that's what has harmed our use of inhaled corticosteroids because. They don't really provide you with an immediate bronchodilator effect, although there's some data showing that you do get some minimal bronchodilation from inhaled corticosteroids.
You definitely get a OA caliber improvements from inhaled corticosteroids because of the reduction in inflammation and a OA, infiltration by inflammatory cells. But the patient's perception is not that they get immediate relief. Also, we've trained generations of people to tell patients that the most important inhaler you have is that bronchodilator.
Because you know when you have bronchoconstriction, it works right away. Carry it everywhere, use it. [00:09:00] Don't ever leave home without it putting your person, blah, blah, blah, blah. So our patients have been educated to believe that's the most important inhaler. When they use it, they feel something, they feel an improvement, and so they've become very reliant on it.
And adherence in asthma to maintenance therapy is very, very poor. So even in people you prescribe maintenance therapy to, they don't really take it. And so what does albuterol monotherapy actually do physiologically? So a. If you overuse albuterol, you get beta receptor downregulation in the smooth muscle, and then you don't even get bronchodilation, so it loses its clinical efficacy.
And, that was demonstrated actually in, the study that was done looking at, giving people Iic s budesonide, Alro versus Alro four times a day for 12 weeks. At the end of 12 weeks, you can see almost no [00:10:00] bronchodilator improvement in the pre post bronchodilator therapy. 2D. Albuterol treatment, so people get beta receptor downregulation.
It turns out that albuterol increases type two inflammation, so actually it's not working as well and it's increasing inflammation. Three, you can get other co concomitant side effects if somebody starts using a lot of albuterol. We know that's one of the treatments we use for hyperkalemia, so you can get electrolyte dysfunction and so forth.
And, more importantly, our patients may have the perception that they're feeling better and not seek care. And this is where we see about 10 people a day dying of asthma. And in my experience, it's not been my severe asthma patients that have died of asthma. It's actually been patients who are mild.
And if you look at the people who end up dying of asthma, having, severe asthma exacerbations. Icu, [00:11:00] a good proportion. About 16% of these people had no symptoms three months before this event. And I guarantee you they were overusing their Saba. Their perception was that their airways were more open, but they're developing cus plugging and edema, and they end up having a fatal or near fatal asthma event.
We also have a lot of good data telling us that Saba monotherapy leads to increase exacerbation, increased healthcare resource utilization. So actually it doesn't, and these patients end up getting more oral corticosteroids. The ones who end up deteriorating and going into the healthcare system. So we really need to shift our thinking because we're perpetuating a treatment that doesn't make any physiologic sense.
It doesn't make any clinical sense, and it inherently is associated with higher risk for our patients. So there's absolutely no reason really to continue this kind of therapy going forward.
[00:11:57] Amy: Mm-hmm. I think, [00:12:00] I think you, you summed it up really well. I mean, I think, as, as someone who, I, I work with a lot of asthma patients, but I think that we, we often don't see the mild, like as a pulmonologist, we often don't see the mild patients.
and so I think a lot of times we're seeing these patients who maybe have. Been to the ICU or they've been using Saba only for years, and I want, do you think that that leads to these, 'cause there's a lot of evidence that you're getting these chronic, like these remodeling changes to the lungs become chronic.
Yeah. Is, is that something that, 'cause I was just like thinking about my practice versus, a a lot of times we don't see the mild patients as well. Mm-hmm. Is, is that something you've noticed?
[00:12:49] Njira: Yeah. I mean, you know, they're in primary care. or even worse, they might be solely in the er. Or urgent care [00:13:00] because, you know, there are in fact socioeconomic reasons why people don't seek care appropriately.
You know, if you work in a job where you don't get paid to be off and go to the doctor and you can't get in during like daytime hours, I think there's a real crisis in terms of access to primary healthcare. you know, it's not as easy as it used to be to get into primary healthcare. So people enter the healthcare system in multiple different ways.
Sometimes it's recurrent urgent care visits. they're urgent cares everywhere. They're open later and on weekends. the emergency room and you know, unfortunately sometimes in hospital. And what we found in our QI work we're doing on a statewide level is that about 40% of the population of patients that have two plus OCS.
A year or an ER visit or a hospitalization. [00:14:00] Don't go to any follow up visits. They purely get their care in those acute care settings. So I think we need, to pair up partner with some of our more urgent care based and emergency room based providers to help them understand that where as we, we know for sure they are not excited about chronic disease management.
Yeah, we are really talking about trading out the rescue therapy, educating the patients at the point of care when they're like a captive audience member and perhaps then you discharge them with an ICS containing rescue so that at least you know that the patient is going to have continued treatment.
Oftentimes, they get a short course of OCS. After that's out of your system, you rebound, you end up going back to an acute care visit. So we need partnerships. We just have to really also meet patients where they are. You know, they're not coming to you and I, they're going to urgent care. They're going to primary [00:15:00] care, they're going to the emergency room, and we need a partnership across the spectrum to kind of target these patients where they enter the healthcare system.
Educate them appropriately and prescribe them the right drug when they leave, so that at least they have what we believe is a superior rescue algorithm. even if they don't, you know, proceed to following up with primary care or subspecialty care, which is often the case.
[00:15:29] Amy: I, I love that phrase, like meeting patients where they are.
I think, was that, did you get that from Dr. Monica Kraft? Because she, she mentioned it in her podcast as well.
[00:15:40] Njira: Yeah, I mean, I think it's, yeah, it's something we're all sort of talking about, you know, we can't, we can't, sit in our, you know, ivory towers and in our clinics and just wait for people to come to us.
We need to partner and find people where they are because [00:16:00] truthfully, it's quite unacceptable given the extent to which we've gone to learn how to manage the disease to still see people dying of asthma. Some of them being children, which is just completely, you know, unacceptable. You know, in our state, for example, three, four years ago, we looked at our data and most, you know, two thirds of the people who died were under the forties, and we did have children that died of asthma.
So I think we need enough, a really different model for how we partner to improve outcomes.
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Time you pass by a tree, maybe give it a little pat on the bark. Now that you know how much it's doing to help you breathe a little easier, learn how [00:17:00] AstraZeneca is creating a healthier society and planet at what science can do.com. I totally agree. And I think just working with my emergency medicine colleagues and our primary care providers, they, it's really.
I, I think they, they are so open to making changes because they see the problem too. and so I think that's a great, like, call to action, is how can we engage these patients sooner? because a lot of times when you know you're getting to the specialty providers. A lot of times, maybe some of that, like you were mentioning, the chronic remodeling and all these changes have become more permanent.
I, so that was, actually one of my questions. So I see, you know, I see a lot of COPD patients and we have another question for you. do you think this model of pairing a bronchodilator with an anti-inflammatory agent could extend to other diseases like [00:18:00] COPD?
[00:18:01] Njira: Oh, I love this question. so. So, I'm gonna say a few things really.
I, I think, you know, we, I feel personally like we've arbitrarily decided that COPD and asthma are completely different diseases. Now, I will preface this by saying that emphysema is a different disease. So I think, I think the, the inherent, differences with people have emphysema and, and truly, even when you see the people with pure emphysema.
In my clinical practice, I don't see them quite as much anymore, but they used to kind of slowly deteriorate, become more hypoxemic and develop, you know, muscle wasting and cachexia, so forth. But in general, they tended not to really have those horrible inflammatory exacerbation, the people with airway disease, I guess in the [00:19:00] way old days they called them the blue blos.
We're starting to see what is the, primary, you know, predictor of exacerbations in COPD eosinophil. What is it in asthma eosinophil? What is the biomarker that predicts response to dupilumab in COPD, eosinophils and pheno? How about in asthma, eosinophils and pheno? You know, what is the pathophysiology of the a OA inflammation we see in these conditions that drive risk?
There are some, you know, very similar factors that drive risk. And so, you know, although we, and, and, and then we have our asthma patients that develop an a OE remodeling process with the, you know, fibroblast driven, that deposition of collagen outside the airways. And the airways become. Not reversible.
And what is that, COD? Or is that asthma with [00:20:00] chronic obstruction? So maybe what we should do is something, you know, I know Ian particularly, but many other people have been pushing over the years, which is why, why don't we focus on the phenotype of the patient? Figure out who has a inflammatory phenotype that's type two driven, which really are the people that benefit.
The most from these kind of strategies, and maybe they are more T two driven patients in asthma, but we know that they're T2 driven patients. In COD, those are the people responding to biologics. We now have dupilumab approved and mepolizumab approved for COPD. So we are starting to see this intersection where targeting the inflammatory component in people who have it.
Leads to improvements in exacerbation. So let's just take one step back, which is, if you have eosinophilic COPD and an exacerbating phenotype, [00:21:00] you should respond well to ICS. I mean, that's, those are the people who in gold, supposed to get ICS and inherently they would have escalation in their T two inflammation in the face of different.
Including viruses, which by the way can really increase T2 inflammation. After that initial t1, then you can get a t2, inflammation and eosinophilia and so forth. So why wouldn't those people respond very well to an anti-inflammatory reliever therapy? Even more important perhaps than this question is, you know, we now know that oral corticosteroids in people with COPD.
Is very, very risky. And I mean, if you really look at the asthma data that David Price published in 2018, you'll see an increasing predominance of metabolic and cardiovascular diseases over time. Now, they repeated this same [00:22:00] work looking at A-C-O-P-D cohort. When diagnosed with CD, follow them to see what happens.
They get increasing dose of oral corticosteroids and five milligram. Now, you know, if you get 50 milligrams for five days, which a lot of people do you already to your 500 milligrams. At 500 milligrams over your lifetime, you see a mortality signal. You see a pneumonia hospitalization signal. You see infection and then you see those cardiometabolic diseases.
So we really should be looking at embracing a treatment paradigm in COPD patients. Maybe not everyone, but if you have eosinophilic COPD or that exacerbating phenotype, we believe you have type two inflammation. I think that's one of those unanswered questions. Should we be treating those patients with anti-inflammatory rescue therapies as opposed to pure bronchodilators, which made sense when we [00:23:00] thought COPD was not a very inflammatory condition, it was more of a broncho, constrictive condition, and now we know better, so we need to do better.
[00:23:11] Amy: I totally agree, and I love, I love how you framed it. and I think we, we do, in the COPD world, we get really, not trying to ruffle feathers, but we get, we get hung up on definitions, I think. Mm-hmm. And, we. The, this, we, there, I think a lot of common processes that are happening in COPD that are happening in asthma.
I totally agree. I think maybe the goal guidelines, like one of the first questions should be, is there inflammation? Because I think that's, that's kind of right. Like that's part of how we phenotype. and I think you gave an example like eosinophils is a sign of inflammation, so I I, I totally agree. We were thinking about unanswered questions for these therapies, that's one of them.
Do you think there's any other things [00:24:00] that need to be focused on in like how we, more questions we need to research or how we can implement this in the going into the future?
[00:24:10] Njira: Yeah, you know, I've spent some time thinking about this. you know, although, scientifically I think it would be quite interesting to know if like people who have.
Not a lot of type two inflammation on the mild asthma spectrum need anti-inflammatory rescue therapies. I worry about making it too complicated because anytime you start, trying to, you know, have we, we, we are teaching our providers, just embrace this. It's so easy. Don't give people type of monotherapy.
If we go back and say, well, let's just see, you know, we, we, let's just see if there's some people who don't need this therapy. Then we may get into a situation where people are very [00:25:00] confused about. Whether or not to give therapies to these patients, but I think that's a fair question. If you consistently have a low nitric oxide level, you are not a eosinophilic allergic person per se.
Maybe you have purely exercise induced bronch. Spasm that, you know, I believe has inflammatory contributions maybe from leukotrienes and so forth. Could that be a person? We don't have any research on these people to see if those are people who should get anti-inflammatory rescue therapy, but you know.
I'm not, I'm, I'm conflicted as to whether it's necessary to start subsegment these patients when we are really trying to get people to embrace a new paradigm. So for sure, we don't have good answers. We don't have a hundred percent. Certainty that a person who purely uses rescue therapy before exercise needs this strategy.
I will tell you, [00:26:00] practically speaking, in clinical practice, I just give everybody anti-inflammatory rescue, because I'm not really checking their inflammatory markers. And, and this was highlighted actually by a study presented at ERS last year where they gave people, they checked the pheno in the clinic.
Then they gave them a machine and said, okay, go home and check your pheno every day. And they did this for a year. But what's really interesting is that in the clinic, that kind of cross-sectional assessment, only about 40% had a high pheno. When you checked it for a year, it was like 85 or 90%, because asthma is a disease of reaction to your environmental triggers.
They infectious, non-infectious, you know, specific or non-specific is the allergens tobacco smoke, or maybe in Michigan, here you have the wildfires in Canada, all of a sudden the air quality indexes bear poor and people having more symptoms. So that's [00:27:00] the tricky part. When you try to start getting too nuanced, you know, we love nuance in the severe asthma clinic.
It's what we live on because we think about asthma all the time. But practically speaking, I don't know that those nuances are helpful on a population level. I think, you know, the COPD question very important. I think there are other questions about what you can do with background therapy. So in the, man, in the mandala study, people were required to stay on their medium high dose iic, s you know, whatever dose, low, medium, or high they were already on.
They had to stay on that. And we saw this overall 20, 7% reduction in exacerbations. The reduction is much more profound in people on lower doses of inhaled corticosteroids. So, you know, now that Gina is really fully embracing this. Concept, hundred percent O [00:28:00] Cs steward. But now we are pushing into ICS steward.
We're saying, you know, we shouldn't people in high dose of inhaled corticosteroids indefinitely. So one study I would love to see. Can we do ICS bearing by adding anti-inflammatory rescue and I'm applying that in my clinic. If I have a person who's fairly well controlled on high dose ICS LABA or medium dose ICS laba, I'm stepping them down and then giving them anti-inflammatory rescue.
Because now I'm confident that I don't have to keep you on the high dose all the time. You can go down and then dose intermittently, essentially giving you a lower dose of inhaled steroid overall. So that's something I think we need to really explore further. And then, you know, the, the studies that were done so far excluded patients on biologics.
So we are participating in a real world study. Where patients are receiving air supra [00:29:00] for, rescue, and it also includes people on biologics. And so maybe we'll get an answer there as to whether people already on biologics would be eligible for this kind of, strategy. So I think as an ICS. Sparing or in the biologics population, the partial responders, you know, these are the questions that I feel are more pressing than perhaps the exercise induced bronchos paths in milder population.
[00:29:29] Amy: So I think kind of what you're highlighting is that, it should really be like the exception, like cases you'd be like, okay, this is, I might consider, you know, a Sabo monotherapy. This is kind of the exception to the rule, like, but the rule should be to have this anti-inflammatory component. Thank you Dr.
Leggo, for a wonderful start to this conversation on anti-inflammatory therapies. Join us for part two of our interview where we dive into the challenges related to anti-inflammatory therapies. we'll also share [00:30:00] some of Dr. Leg Gogo's professional journey and insights on pursuing a research career.
See you then.
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