This transcript has been edited for clarity.
Michael Wechsler, MD: Hello and welcome to Medscape's InDiscussion series on moderate severe asthma. I'm Dr Mike Wechsler, and this is episode six of the first season. Today we'll be discussing the treatment of moderate to severe childhood asthma. We've had a great series so far with some great guests, and we've gone through already precision medicine in asthma, the PrecISE network, and how to develop clinical trials in asthma, some advances in severe asthma treatment, multidisciplinary approaches to treatment, as well as environmental and social determinants in asthma. Today, to discuss pediatric asthma and advances in severe childhood asthma, we've got two amazing guests, my friends Dr Len Bacharier and Dr Wanda Phipatanakul. Welcome, both of you.
Wanda Phipatanakul, MD: Thanks, Mike.
Len Bacharier, MD: Thanks, Mike. Great to be here.
Wechsler: It's great to have you both. Len Bacharier is a professor of pediatrics, allergy immunology, and pulmonary medicine and scientific director for the Center for Clinical and Translational Research, and he's the Janie Robinson and John Moore Lead Chair in Pediatrics at Vanderbilt University Medical Center. Wanda, Dr. Phipatanakul, is an attending physician and director of the Research Center in the Division of Immunology. She's the Westonian Endowed Professor of Pediatrics at Harvard Medical School. Welcome to InDiscussion. What can each of you share with our listeners that many people don't know about you? Wanda, why don't you start? Tell us something special that we should know about you.
Phipatanakul: Okay, so a lot of people know that in my day job, I do a lot of research in the area of asthma and allergy and I'm an allergist, and I've been in Boston for 22 years. But I guess some things people might not know about me is that I'm from St Louis. I grew up in St Louis and I'm an avid Cardinals fan. I also love to run. I'm a runner and have run marathons, but not so many recently. I also play the harp and piano.
Wechsler: Wow … all right! Maybe at the end, you can play us a little ditty on one of your instruments. Len, tell us something about you that's special.
Bacharier: I am an avid Cardinals fan as well, having spent more than two decades in St Louis, so Wanda and I have that significant commonality. Something folks probably don't know is that we have an adopted rescue dog named Ginger. She's our little pit bull who we saved from the streets of St Louis now 8 years ago. And she's been a wonderful addition to our family and has introduced us to the world of veterinary medicine, with a variety of medical challenges that only the pet of a physician could have.
Wechsler: Great. Well, it's great to have a couple of Cardinals fans. I'm a huge Red Sox fan, and I think last time we met in the World Series was 2013, and the Red Sox beat the Cardinals. In any case, let's move on. I think you all know that I treat a lot of patients with severe asthma, but I really focus on adult patients. I occasionally see some pediatric patients. Tell me, how are adult patients different from pediatric patients with severe asthma?
Phipatanakul: One thing we always to try to highlight is that kids are not just little adults — they don't just have smaller lungs. They are developmentally different; a lot of times their pathophysiology is different. I would say they're still young, their lungs are developing, and their immune system is developing. So, a lot of the more fixed features that you see in adults are not quite there yet. Lung function tends to be preserved, and they tend to have more allergic phenotypes. They also change over time, probably more than the adults. Len, any other thoughts on that?
Bacharier: I think those are all important distinctions. One of the points that you mentioned is that allergy is a cornerstone of childhood asthma and really a centerpiece to how it should be evaluated, thought about, and managed. The other point is that most children present with exacerbation-dominant disease, more so than day-to-day symptom-dominant disease. I think that's an important distinction because it lulls physicians and parents into a false sense of complacency because [patients] have periods of apparent wellness, because they're not in the midst of exacerbation. I really do think that keeping both the concepts of allergy and exacerbation proneness in your mind as you think about the child with more moderate to severe asthma is essential.
Wechsler: Yeah, I think that's got to be tough. You mentioned the parental component, and I view that as one of the challenges in asthma. How often are you treating the kid and how often are you treating the parent when you deal with pediatric patients with severe asthma and other diseases?
Phipatanakul: I think the parent is a huge component, especially when they're younger. You're depending primarily on them for the history, what types of symptoms they have, and the child can't even really comment. Also, in the little ones, they're not able to do good spirometry, so we have more challenges in understanding objective markers. And then, like Len said, they're different. Often in between, they'll be totally fine and have great lung function and then crash and burn with those exacerbations. This is a bit different than some adults who chronically have symptoms, or they have a lot of variation … being well and exacerbating.
Bacharier: Yeah. And I think it's about treating a family. I don't view them as individual patients; it's the entire family that's involved here. It's not just the mother and the child, it's grandma, it's the extended family. We often have to bring the schools into play and bring school nurses into play in order to provide the broadest coverage to assure that our not-so-simple treatment regimens can be used in the most effective way to yield the best results.
Wechsler: Not to mention the fact that, generally, parents can be a bit more sophisticated and avoid things that are known to cause problems. Kids may not be that sophisticated, may not appreciate or may not do as good a job in avoiding things. I'm guessing that also can be one of the challenges. What are some of the other challenges in pediatric asthma in particular?
Phipatanakul: Thinking about the long-term effects of these drugs [in] kids [who] are still growing; they're still developing. There are a lot of challenges with systemic side effects from many of the high doses of inhaled corticosteroids and systemic corticosteroids that we give these kids, and just a few doses can cause significant long-term impact.
Wechsler: Let's go through some of the data there. When giving kids inhaled corticosteroids, which is, I'm guessing, the mainstay of treatment for most of the pediatric asthma that you see, how common are side effects? What are the most common side effects that you see, Len?
Bacharier: Truthfully, the medicines we use are remarkably well tolerated. And you know, while I'll explain the long list of potential side effects, including thrush, voice changes, appetite changes, and weight gain, that can come with the inhaled corticosteroid use, they're really pretty infrequent and pretty difficult to detect. The literature supports a modest effect on linear growth. This is on the order of a centimeter, which for most folks has no practical impact on their lives. I lay it all out for them and stress that we've got decades of experience that really do reinforce the overall safe profile of these medications. Their use really can be life-changing for the majority of patients, once the families become comfortable that these medicines are safe and effective.
Wechsler: What about the use of inhalers in kids? How easy is it to teach kids how to use inhalers? And how much of a problem in the severe asthma patient population in pediatrics relates to improper technique, not to mention lack of adherence, but just improper technique and getting the drugs where they need to go.
Phipatanakul: I think that's a significant challenge to use the inhalers properly, particularly with the little ones. There's a lot of education and reinforcement needed to have the right air chambers and spacers, and to get a kid to sit still for a neb [nebulizer] is challenging and very complicated. When you think about the dry powder inhalers vs the ones with the AeroChambers, there is a lot of variation.
Wechsler: At what age can you get your patients to do spirometry reliably? And also, in the same vein, at what age can you definitively say that a patient has asthma vs, say, bronchiolitis or recurrent viral infections or something along those lines? How do you guys make those determinations of when it's asthma vs bronchiolitis?
Phipatanakul: Well, it does depend on the kid and their development. Some children are doing spirometry reasonably well at age 4 and 5. But really, 5- and 6-year-olds and, in some populations, even 6- and 7-year-olds have difficulties. I think that there's a variation. In general, we don't really go with that bona fide diagnosis of asthma probably until after age 4. You have these recurrent wheezers earlier than that. And maybe sometimes they do declare themselves at age 2 or 3, but reliable spirometry can be challenging. Even some older kids and adults have difficulties. There is airway oscillometry that we've been using more in some of our studies and they're really trying to have more widespread use of that and it's a little bit easier to use. And I've been doing it on 2- and 3-year-olds in another study that we're doing.
Bacharier: I think it's really challenging. You know, there are no established standards for the diagnosis of asthma in children, especially in younger children. I'm very comfortable giving a 1-year-old a diagnosis of asthma if they have the appropriate symptom complex I've evaluated the differential diagnosis satisfactorily, and I'm confident they don't have a secondary condition that would explain their disease, because a diagnosis of asthma in a young child doesn't mean they're going to have asthma forever. We see asthma improve. It doesn't need to be a lifelong diagnosis that you're establishing at age 1 or 2. But if you're going beyond the most low-step therapy for patients, I think it's helpful for the families to understand that this is really asthma that we're treating because we're using asthma medicines to manage it. In the setting of concomitant allergy with an appropriate differential diagnosis that's been assessed, I'm very comfortable ascribing that diagnosis as early as it's clear that it's appropriate.
Wechsler: Do kids grow out of asthma? That's a question that comes up often. Do the kids grow out of asthma or did they not have asthma to start with or will it just persist or is there more of a bimodal? They might have it as children as they grow and don't get better, and then they have this predisposition that will get worse again. What are your thoughts?
Bacharier: I think it's all of those. I mean, I think more children outgrow their pediatricians than outgrow their asthma.
Bacharier: And we know adolescent boys tend to get better for some period of time, but many of them in early adulthood encounter the wrong respiratory challenge, be it a viral infection or whatnot. It comes back and then it's there for the remainder of their lives. I think it can have periods of apparent remission that is probably unrelated to therapy. I think that we're not making lifelong diagnoses here. These are diagnoses that help direct therapy. And having an appropriate diagnosis gets patients on the right therapy, which is what they need, regardless of what you want to call it.
Wechsler: We've talked about how asthma evolves in younger children. Let's talk a little bit about your treatment approach to these kids. I know that there's the Global Initiative for Asthma Guidelines. There are the NAEPP (National Asthma Education Prevention Program) guidelines. Maybe you can walk me through your approach to patients with asthma. When do you use leukotriene modifiers and everything up to the biologics? Tell me what your general approach is.
Phipatanakul: We start out with as-needed albuterol; the new guidelines for the little ones is that you use inhaled corticosteroids as needed with viral infections. You can add maintenance inhaled corticosteroids as probably the next step, and leukotriene modifiers sometimes in between or earlier, and then with the higher steps we're really pushing more, especially in school-age kids, this maintenance reliever therapy, which is the ICS [inhaled corticosteroids] formoterol, which is an ICS LABA [long-acting beta agonist] and then going to medium dose and then high dose and adding, for some other children (6 years of age and above), long-acting muscarinic antagonists. Once you have all those — ICS, LABA, and high doses — then you start thinking that they're in step five and then it's the biologics.
Wechsler: So, Len, what proportion of your pediatric asthma patients continue to have symptoms, continue to have exacerbations on inhaled corticosteroids, long-acting beta agonists, plus or minus a third agent?
Bacharier: It's certainly less than 20%. And that's in a patient population that's a referral population to an academic medical center. I think the vast majority of patients are extremely effectively managed with conventional therapy — with ICS, with or without a LABA component. But there is a subset, 10%-20%, who, despite those therapies, just don't get to where we think they should be.
Wechsler: This is an exciting era in the management of asthma. Just in the last 7 years, we've had five different biologics approved. Before that, we had anti-IgE therapy with omalizumab. Let's go through the biologics that are approved in the pediatric age population and what age ranges they're approved for and how do you decide to use them? Which ones are approved now down to age 5?
Phipatanakul: Okay, this has been an exciting area. The first biologic is omalizumab or anti-IgE, which came out in 2003, and that's approved now down to age 6. It's approved for home and in-clinic visits and given every 4 weeks. The dosing is based on weight and total IgE level. The interesting [thing] about omalizumab is that it's also approved for other things. It's approved for chronic urticaria in kids 12 years and above. It's approved for nasal polyps and chronic rhinosinusitis in adults and there are more indications. That's sometimes what we think about — the same biologic can treat other conditions. The next one was mepolizumab, that's an anti-IL-5 [anti-interleukin-5] that works on eosinophils; that's approved down to age 6. So, there are none approved down to age 5, Mike, in answer to your question; they are approved to age 6. Mepolizumab is given every month with a fixed, standard dosing. It can be given at home and in the office as well. Then there's benralizumab, which is approved down to age 12, which works in the IL-5 receptor and blocks IL-5, which works on eosinophils. These are all targeting type 2 inflammatory asthma.
Wechsler: Len, tell us a little bit about the dupilumab studies.
Bacharier: We were very fortunate to have completed an international trial that led to the approval of dupilumab down to the age of 6 [years] in children who have asthma with an eosinophilic phenotype. It is administered every 2 weeks, either in clinic or at home. I think it adds substantially to our armamentarium. As a therapy that reduces exacerbations, improves lung function, improves asthma control, and improves quality of life, I think that really is another addition. Like several of the other biologics, it has indications and positive effects in comorbid conditions. The most dominant one that we see is atopic dermatitis. So, one therapy improving more than one disease state that actually frequently co-occur with asthma. The others are a little less common. We don't see a lot of chronic rhinosinusitis nasal polyps in younger children, but I do think atopic dermatitis is an important one. Then, most recently tezepelumab, or anti-TSLP, has been approved for patients 12 and above without regard for understanding their underlying immunophenotype; it is able to reduce some exacerbations and improve lung function. I think most of us have little experience with it in the adolescent space, and it still needs to be studied in younger children. But I think we now have an impressive collection of these advanced therapeutics that are based on the patient's phenotype and other family and patient characteristics and that you can make a treatment decision around. Most patients who qualify for one of these qualify for multiple of these. And how to make a precise, accurate determination is still a bit up in the air.
Wechsler: How do you choose between them, Wanda?
Phipatanakul: These are all great questions. A lot of it you go by the age of indication, and then if they have other comorbid conditions. A lot of times, I see patients with bad eczema and I start thinking about dupilumab because it was first indicated for atopic dermatitis and has been approved all the way down to 6 months of age. Frequency of dosing is also something to think about with kids. The dupilumab dosing is every 2 weeks; omalizumab is every 2-4 weeks, depending on weight and IgE level, and the anti-IL-5 is every 4 [weeks], and benralizumab is every 8 weeks. We consider frequency of dosing, whether you can give it at home vs the clinic, whether the parent feels comfortable doing home administration, and the other comorbid conditions. The teze [tezepelumab] is interesting because it might help some patients with a non-type-2 or type 2–independent asthma. I've seen some of those as well, but not as often. It's mostly allergic triggered, but we've seen some, particularly with certain genotypes that we've found more commonly in African Americans and Hispanics that actually are non-type-2 and it's possible that tezepelumab would be beneficial in that case. It's shared decision-making; you talk with the family about the pros and cons of the different ones. Like Len said, they often go either way. I just had a case yesterday and we decided because he had so many other allergic components, he really wanted to try the omalizumab. At first, he was hoping it would help his food allergies, even though it's not FDA approved [for that indication].
Wechsler: Is there any role for these novel biologic therapies, perhaps, in preventing asthma and what's going on in that research space?
Phipatanakul: Well, yes, you know, I'm leading what's called the PARK study, which is the prevention of asthma in high-risk kids. It's an NIAID-funded study that's treating high-risk allergic kids down to age 2, so 2- and 3-year-olds are being treated with omalizumab vs placebo for 2 years, and then we'll follow them for 2 years off therapy and see if we can prevent asthma — that's the primary outcome. We are also going to be looking at, as a second primary outcome, whether we modify or alter the progression of the disease by reducing severity in some of the kids who do develop asthma. And then we'll have the opportunity to look at the whole atopic march. What happens when a child's immune system is not fully developed and they don't have all the characteristics like adults do, and you intervene with the IgE-mediated pathways by blocking IgE, can you prevent other allergic diseases too? We'll look at food allergy and atopic dermatitis and rhinitis, but asthma is the primary outcome.
Wechsler: Wow, that's exciting and could be paradigm shifting for our management. Well, we're coming to the end of our time. Before I thank you guys for participating, maybe you can give me your thoughts on some of the key advances that you see in the future of severe asthma in children? What direction are they heading? Len?
Bacharier: This is really a wonderful time if you are ever going to have severe asthma as a child. This is when you want it because we really have safe and effective approaches. I think we still need much more data to understand the place of these agents in the management of disease. And while we talked about disease modification in young children, there's reason to think that maybe disease modification could occur in older children, contrary to what has been seen in adults, where these therapies work as long as you take them. And then as soon as they're pulled away, the effects evaporate into the clear blue sky in the majority of cases. I think better understanding of how to phenotype these patients, understanding which approaches to apply, and then starting to understand whether we can begin to pull them away at some point and see if we've modified the underlying disease in some way. I really think that's something that we should retain hope around and not just presume that these agents will lose their effect when they go away. They might but I think we should study it more carefully to really understand.
Wechsler: I agree. Why don't we close on that note … this is really an exciting time for the management of pediatric severe asthma, and this has been a great discussion. And I want to thank both of you for joining us today for episode 6 of this great series of InDiscussion. Today we've had national asthma experts Drs Len Bacharier and Wanda Phipatanakul discussing with us the treatment of asthma in the pediatric population. Thank you to our listeners and thank you both for joining us for this engaging discussion.
Phipatanakul: Thanks, Mike.
Bacharier: Thanks, Mike. It's been a pleasure.
Phipatanakul: It's been fun.
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Cite this: Challenges and Opportunities: Treatment and Prevention of Moderate to Severe Childhood Asthma - Medscape - Dec 06, 2022.