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CME / ABIM MOC

Catching Our Breath in Moderate to Severe Asthma — Expert Updates for Pediatric Patients

  • Authors: Stephen J. Teach, MD, MPH; Leonard B. Bacharier, MD
  • CME / ABIM MOC Released: 9/15/2022
  • Valid for credit through: 9/15/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

    You Are Eligible For

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    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for pediatricians, allergists and clinical immunologists, and pulmonologists.

The goal of this activity is that learners will be better able to advance asthma care in pediatric patients who are uncontrolled by their current treatments.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Management of moderate to severe asthma in pediatric patients
  • Have greater competence related to
    • Applying tools to evaluate asthma control in pediatric patients
    • Implementing biologic treatments for pediatric patients


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Faculty

  • Stephen J. Teach, MD, MPH

    The Wendy Goldberg Professor
    Children's National Hospital
    Professor and Chair
    Department of Pediatrics
    Associate Dean for Pediatric Academic Affairs
    George Washington University School of Medicine and Health Sciences
    Washington, DC

    Disclosures

    Stephen J. Teach, MD, MPH, has no relevant financial relationships.

  • Leonard B. Bacharier, MD

    Janie Robinson and John Moore Lee Chair in Pediatrics
    Professor of Pediatrics
    Director
    Center for Pediatric Asthma Research
    Scientific Director
    Center for Clinical and Translational Research
    Section Chief
    Pediatric Allergy and Immunology
    Division of Allergy, Immunology, and Pulmonary Medicine
    Monroe Carell Jr Children’s Hospital
    Vanderbilt University Medical Center
    Nashville, Tennessee

    Disclosures

    Leonard B. Bacharier, MD, has the following relevant financial relationships:
    Consultant or advisor for: AstraZeneca Pharmaceuticals LP; DBV Technologies; Kinaset; Regeneron Pharmaceuticals, Inc.; Sanofi; Vertex Pharmaceuticals Incorporated
    Speaker or member of speakers bureau for: GlaxoSmithKline; Regeneron Pharmaceuticals, Inc.; Sanofi

Editors

  • Iwona Misiuta, PhD, MHA

    Medical Education Director, Medscape, LLC

    Disclosures

    Iwona Misiuta, PhD, MHA, has no relevant financial relationships.

  • Frederick Stange, DO

    Scientific Content Manager, Medscape, LLC

    Disclosures

    Frederick Stange, DO, has no relevant financial relationships.

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

Catching Our Breath in Moderate to Severe Asthma — Expert Updates for Pediatric Patients

Authors: Stephen J. Teach, MD, MPH; Leonard B. Bacharier, MDFaculty and Disclosures

CME / ABIM MOC Released: 9/15/2022

Valid for credit through: 9/15/2023

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Activity Transcript

Stephen J. Teach, MD, MPH: Hi, everyone and welcome. My name is Dr Stephen Teach, and I'm chair of the department of pediatrics at the George Washington University School of Medicine. I'm also a practicing pediatrician and pediatric emergency medicine doctor at Children's National Hospital in Washington, DC. I've had a long-standing interest in asthma, particularly as it affects underresourced and largely minority urban children in the District of Columbia and across the nation. Joining me today is Dr Len Bacharier, my long-time friend and colleague. Len, why don't you introduce yourself?

Leonard B. Bacharier, MD: Great, thanks, Stephen. Pleasure to be here. Pleasure to share the time with you and our friends. I'm Len Bacharier. I'm a pediatric allergist-immunologist, a professor pediatrics, and the Janie Robinson and John Moore Lee Chair in Pediatrics at Monroe Carrell Jr Children’s Hospital in Vanderbilt, in Nashville, Tennessee, where I direct the center for pediatric asthma research and the center for clinical and translational research, and my career has really been focused on understanding the inception, development, and management of asthma in children. And I really look forward to our discussion today.

Dr Teach: Great, glad to be with you here today, Len. So, asthma is a chronic disease. It's marked by variable inflammation and swelling of the small- to medium-sized airway. That swelling occurs in response to a variety of external agents, principally allergens, principally perennial, but also seasonal allergens, and also irritants, the most common of which is environmental tobacco smoke. So, this has a degree of constant inflammation and swelling of those airways, and then that can be exacerbated and there can be a rather abrupt increase in that variable swelling and inflammation, and the child can have an exacerbation, what we used to call an asthma attack. So, more than 5 million children nationwide in the United States affected by this incredibly common disease. It results in really marked morbidity, greater than 10 million missed school days per year, hundreds of thousands of emergency department visits every year, and hundreds of thousands of hospital admissions.

So great morbidity, great cost. And much of this has been very persistent through time. It has also been marked by dramatic disparities: disparities both in the delivery of care and in health outcomes. This is a disease which disproportionately affects, for example, Black children and families who not only have a higher prevalence of the disease, but higher morbidity. And so, they have more emergency department visits, more exacerbations, and more missed school days. So, Len, a lot of opportunity for improvement. We're going to walk today through kind of the state-of-the art pediatric asthma management. But I think it's important to stay close to our roots here. And I know you share this interest with me, which is the underresourced urban child and family who struggle so much. We are actually going to start with a case of a child that you and I discussed recently from your own practice there in Nashville.

This is an 8-year-old. He's an urban Black male on Medicaid insurance, and he's got asthma and he's had it for a while. It was initially diagnosed when he was a toddler, just at age 2, but he's really had symptoms since infancy. Currently he averages monthly flare-ups with a total of 6 oral corticosteroid courses in the last 12 months. He has daily symptoms of cough, wheeze, and these are increased with activity like running around on the playground or playing football with his friends. He has nightly cough, and he actually wakes up and wakes his parents up 1 to 2 times a week. He's had 6 emergency department visits and 3 hospital admissions in the last 12 months, never to the pediatric intensive care unit (PICU), and he's never been intubated. And he is missed 22 days of school, 22 days of second grade in the last academic year. He lives with his single mom in multiunit public housing where he has 3 siblings, all of whom have various degrees of atopy. This is a 2-bedroom apartment, and he shares the bedroom with his 3 sibs. Mom smokes cigarettes daily but says she does her very best to smoke outside. She reports mold, roaches, and mice in the apartment, and she relates, a little tearfully, the recent death of the child's maternal grandmother and a cousin he was close to.

He has comorbidities: allergic rhinitis, moderate atopic dermatitis, eczema. He has had in the past, ordered by his primary care pediatrician, an abnormal polysomnogram. And he is going be following up with the ear nose and throat service there in Nashville. He himself has a negative screen for depression and seems to be by history at low risk for gastroesophageal reflux. His approach to therapy by his primary care pediatrician to date, it's been a reasonably aggressive application of the stepwise therapy that you'll be talking about a little bit later. But, this is a child initially started on budesonide 0.5 milligrams twice daily (BID) by nebulizer when he was a younger guy. And then most recently, he's been on a combination therapy of an inhaled steroid with a long-acting β-agonist in this case mometasone-formoterol 100/5.

He's recently actually been bumped up to mometasone-formoterol 200/5, and he does take montelukast a chewable tablet 5 milligrams at bedtime with reasonably good adherence. He also takes cetirizine and intranasal fluticasone as needed for his allergic rhinitis. So, this is a rather extreme case of asthma that despite aggressive approach to stepwise therapy, Len, we just haven't yet gotten this child the under control. And I think it is also, Len, a good example of the potential disparities that we see in outcome of many urban children with asthma. And I'm just going to share a recent slide from our own group here. You'll recognize Washington DC, and on the left, you have our most recent map of the at-risk emergency department (ED) visit rates for asthma.

So, these are ED visits for asthma among kids with asthma in the district of Columbia. And the dark color here is bad. That's where their rates are, are really high. And you'll see those high rates concentrated in the Southeast part of the district. And that's a district challenged by a lot of adverse social circumstances. More and more you're seeing those adverse social circumstances for children quantified in something called the Child Opportunity Index. On the right, you'll see the Child Opportunity Index again, with a map of the district mapped for census tracks and here a low opportunity index is the light color. And the white color is where it's very low. And you'll see that those census tracks heavily concentrated, where the at-risk emergency department visits for asthma are their highest. And so that correlation is quite striking and has been reproduced in multiple urban environments nationwide. So that's the context for a lot of exacerbations this child has had. Can you talk a little bit, Len, about how those exacerbations put the child at risk? For example, what is the effect of repeated bursts of oral corticosteroids in children?

Dr Bacharier: Yeah, thanks, Steven, for really putting this all into a very clinically relevant context. What we've really become increasingly aware of over the last decade or so is that both acute and cumulative toxicity that comes with oral corticosteroids. These have been our go-to strategy for the rescue of children during exacerbations of the greatest severity, but even less-severe exacerbations. And this is a trial or a large study from Taiwan where they evaluated the risk of adverse events within 30 to 90 days after a single course of prednisone for asthma. And what they found were statistically significant, increased risks of gastrointestinal (GI) bleed, pneumonia, sepsis within 90 days of a single course of oral steroids. And I think what we'll spend most of our time today talking about are strategies to avoid excessive or frequent, or better yet, even infrequent use of oral corticosteroids to both minimize the risk of exacerbation, but also these adverse consequences of exacerbation beyond those related to asthma itself.

Dr Teach: Absolutely. And it's important to remember, as well, that for every emergency department visit for asthma, there's something like 10 to 15 missed school days on a population basis. So really quite extraordinary, the multiple medical and social impacts, potential and real adverse events, from asthma not to be taken lightly for sure. Now, Len, we, you and I, both know that really evaluating a child and managing a child really requires careful and ongoing and repeated assessment of their asthma control. So, can you talk to us a little bit about how you think about that?

Dr Bacharier: Sure. So, asthmatics are all very well trained. And when asked other than in extremists, how an asthmatic is doing, they all answer with the exact same single word response, fine; and fine is really not very helpful to those of us trying to help manage their disease. And what we've learned over time is trying to come up with objective measures that really do help classify and help families think through the extent and impact of asthma symptoms are actually quite important. And 1 example of this is the childhood asthma control test. This is one of several available validated tools that we find helpful in clinical practice, that can be completed by the child and the family, that ask them very specific questions with quantitative responses, that really then allow you to understand where their control lies relative to a standard panel, and then allows you to track these features over time.

So, for example, this childhood asthma control test has a few questions that the child will complete. The child does not have to know how to read because there are facial expressions that they can link to that talks about how is your asthma today? How much does your asthma impact your ability to run, exercise, or play sports? Do you cough because of your asthma? Do you wake up at night because of your asthma? It then has 3 questions that the parent completes that help round out this experience. And it's asked how many days in the last 4 weeks have they had symptoms, how many days did the child wheeze and how many times did the child awaken at night due to asthma? You add up all of these and you get a score that ranges anywhere from 0 to 27. Scores of 20 or higher are associated with well-controlled asthma. Scores of 19 or lower are associated with not-well-controlled asthma. And it gives you a very quick and easy guidepost to determine where the discussion should go from here. So, I think this is really an important tool for families to use during every clinic visit. They can fill it out in the waiting room or waiting for you to come in, to enter the exam room. You walk in and in 1 second, a quick glance at this tells you exactly where you are and where you need to direct the discussion.

Dr Teach: I agree, Len, and I've found this to be so useful within our asthma practice and the families get to be very familiar with it. And, and every time they come, they seem to be able to fill it out more quickly. And they're very interested in seeing how their numbers rise and fall in response to changes in season, changes in therapy. So, I agree a hundred percent. It's an awesome tool. Yeah.

Dr Bacharier: One of the other things that I have done is after you make an intervention, I ask the families to do this at home in a month. And I say, if you get a score of 20 or higher, we did our job. And if you get a score of 19 or lower, I want to hear from you in a month, not see you in 4 months where you've had 4 more months of poor control. It's a quick way for them to see where they are and to provide objective feedback rather than 'I'm just not doing so well,' or 'I'm doing fine.'

Dr Teach: I agree. It's a great tool, a great approach.

Dr Bacharier: Yes, agree. Now, after gaining an understanding of your patient and their family’s perspectives on how well-controlled the child’s asthma is using the Childhood Asthma Control Test, it is important to utilize objective measures to assess asthma control. The currently available objective measures of asthma control recommended by the American Academy of Pediatrics are assessment of lung function, evaluation of airway hyperresponsiveness, and biomarkers. Assessment of lung function can be done using tools like spirometry or by measuring peak flow. Evaluation of airway hyperresponsiveness may be assessed by bronchial provocation tests with pharmacological agents such as methacholine, or non-pharmacological stimuli such as physical exercise. Biomarkers of inflammation related to asthma include exhaled nitric oxide and eosinophils in peripheral blood.

It is important for pediatricians to subjectively and objectively assess a child's asthma to determine the next approach for managing the patient, especially if the patient has uncontrolled asthma.

Dr Teach: You know, we're going to spend the balance of our time today, really talking about pharmacologic approaches to advanced asthma care in children with moderate to severe and particularly uncontrolled disease. But I think it is worth mentioning the many nonpharmacologic approaches to asthma care. We need to mention them, but we need to be rather modest in our expectations from these. So, what am I talking about? I'm, I'm talking about, data on trigger control and interventions targeting maternal and child depression, stress, and anxiety. So, for example, the association between environmental tobacco smoke and pediatric asthma and morbidity is really striking, but effective interventions to reduce secondhand environmental tobacco smoke exposure among kids with asthma are limited. And the data there to suggest that this is a magic bullet, if you will, to asthma control are pretty limited.

Similarly, the latest guidelines from the National Institutes of Health published in 2020 on the role of allergen reduction -- they stress their limited efficacy and really make note that it is really multidimensional interventions in children known to be sensitive and exposed to specific allergens that will actually be effective for kids. And finally, the role of interventions targeting, as I said, maternal and child depression, stress, anxiety, all of which have been repeatedly shown to be associated with worse asthma outcome data on the efficacy of interventions, addressing those, again, [are] quite limited. So, although there are a lot of nonpharmacologic approaches to asthma care, unfortunately, their efficacy in clinical practice has not been well demonstrated, which takes us to pharmacologic therapy, and a lot of this today is best based on these, these stepwise therapies recommended both by the National Institutes of Health and the Global Initiative in Asthma. Len, can you walk us through that concept?

Dr Bacharier : Sure. Steven, so, you know this is the general asthma approach that we've now, I think, all become very comfortable with over the last decade or 2: this stepwise approach of determining where your patient is, assigning a level of therapy, evaluating clinical response, and then based on the response or lack thereof, an escalation of steps until you achieve the desired level of asthma control. This is a child who is already receiving medium-dose inhaled corticosteroid/long-acting β-agonist (LABA) therapy in addition to a leukotriene receptor antagonist. He's already at step 4, and despite his step 4 therapy, he clearly is not meeting the goals of asthma care [with] repeated exacerbations, ongoing chronic symptomatology. So, he would definitely be a child for whom the step 5 interventions would be considered.

I think what's essential in this age group, is that in step 4, all patients should really be referred for expert asthma specialist advice, and that specialist advice would include the phenotypic assessment of asthma to look for evidence of what we will discuss shortly as type 2 airway inflammation, consideration of whether an even higher dose of inhaled corticosteroid might or might not be beneficial, [and] the consideration of add-on therapy with one of the biologics that are available for the management of asthma. This is really the well-accepted strategy for becoming a more personalized phenotype-driven approach. Even in children as young as 6 years, we're going to talk about type 2 inflammation and the indicators of that: evidence of eosinophilia in the peripheral blood or elevation of nitric oxide, a marker of type 2 inflammation in the exhaled air, are the 2 most clinically relevant markers for type 2 inflammation.

Dr Teach: We have pivoted, I think, Len, to this concept of biologic therapy, modification of the child's immunologic response. Can you walk us through, Len, the immunologic pathways that underlie the inflammatory basis of asthma?

Dr Bacharier: We know that the inflammation that underlies asthma is driven by both innate and adaptive immune responses and can manifest itself as both type 2 high asthma, an asthma state associated with type 2 inflammation, or type 2 low asthma, where there's very little evidence of type 2 inflammation. Type 2 inflammation is the inflammation derived from type 2 immune cells, both adaptive and innate. These immune cells produce large amounts of 3 central type-2 cytokines: interleukin (IL)-4, IL-5, and IL-13. When produced by either the innate or the adaptive system, these cytokines then have several downstream effects. IL-5 is the predominant cytokine that drives eosinophil development, differentiation, [and] survival, and is essential for the development and persistence of eosinophilic inflammation. IL-4 and IL-13 are important for B-cell development, class switching, and the development of IgE, which is then essential for the allergic immune response after loading the surfaces of mast cells and basophils. IL-13 has also become evident as a dominant cytokine in the airway leading to impacts on airway structural cells and the upregulation of inducible nitric oxide synthase, which then leads to the production of nitric oxide. But also, there's a nonspecific pathway that follows airway inflammation that is driven by a collection of molecules called the alarmins: thymic stromal lymphopoietin (TSLP), IL-33, IL-25.

When activated, these alarmins also affect type-2 cytokine-producing innate lymphoid cells (ILC2s), which then drive more IL-5 and IL-13 production and all of those downstream effects. In children, especially in this age group, the type 2 high asthma state is really the most common and dominant state. There is a well-described type 2 low state, but that is more of an issue in our adult patients than we see in children, but in children who don't seem to have evidence of type 2 inflammation that does need to be a consideration.

Dr Teach: Len, the immunology is complex, for sure, and that actually presents us with an opportunity, right? Because it provides us with multiple opportunities to interrupt this immunologic inflammatory cascade with these new biologic therapies. So, can you talk to us a little bit, Len, about the current biological therapies approved for children and how they target different aspects of type 2 inflammation?

Dr Bacharier: Yeah, of course. So, so we're very fortunate that at the present time we have 3 Food and Drug Administration (FDA)-approved biologic therapies, monoclonal antibodies directed against specific immunologic targets that have demonstrated clinical ability to improve relevant asthma outcomes. The 3 that we'll focus on are omalizumab, a monoclonal antibody directed against IgE. It binds IgE preventing its ability to bind to the surface of mass cells and basophils. IgE is an inert molecule unless it is associated with a mass cell or a basophil. So, this really does block the allergic response in a very profound and effective manner. We have mepolizumab, a monoclonal antibody that bonds to soluble IL-5. By binding IL-5, it impairs and blocks its ability to interact with the IL-5 receptor on the surface of eosinophils. Eosinophils that are starved for IL-5, fail to develop, fail to survive. This leads to a rapid and profound decrease in peripheral blood eosinophils. We see improvements in multiple asthma outcomes. Finally, dupilumab is a monoclonal antibody that binds to the IL-4 receptor ɑ-chain, a chain that is shared between the receptors for both IL-4 and IL-13. So, this single monoclonal antibody blocks all the downstream effects of both IL-4 and IL-13, and therefore also has substantial clinical effects in patients with asthma and evidence of type 2 inflammation.

Dr Teach: So, a lot of agents available, probably more coming in the future. Can you just briefly, Len, run through some of the recent studies which have demonstrated the efficacy of these agents?

Dr Bacharier: Sure. So, let's just take a high-level view of those three agents. The first one that we had available to us was omalizumab, this anti-IgE monoclonal antibody. What we'll see here is an example of a trial done in children very similar to the child that we discussed earlier. These are inner-city children with allergic asthma uncontrolled with standard therapy to whom either omalizumab or placebo was added. These were given as injections over a 1-year period, and what the investigators saw was a statistically significant reduction in both symptom-days at about a half a day every 2 weeks, and a significant reduction in asthma exacerbations of nearly 20% with a near-complete blunting of those peaks of exacerbations that we have all seen in the spring and fall season.

So here, we see evidence that omalizumab improves both symptom control and exacerbation rates in inner-city children with uncontrolled allergic asthma. Similarly, in a study recently completed in a population again of inner-city children with exacerbation-prone eosinophilic asthma, we added mepolizumab, an anti-IL-5 antibody, to standard therapy in a group of children, 6 to 17 years of age, and demonstrated that mepolizumab therapy over a year resulted in a 27% reduction in the risk of exacerbations compared to children receiving placebo. We did not demonstrate any effects on lung function, but, importantly, we did not identify any unique safety signals from mepolizumab in this age group. Finally, we also recently reported on the effects of dupilumab, the anti-IL-4 receptor ɑ antibody as a step-up therapy in children, 6 to 11 years of age with an uncontrolled moderate severe asthma, generally with a type 2 pattern. This was an international trial, so a worldwide study of over 400 children. And here, we also demonstrated a significant reduction in severe exacerbations of asthma, greater than 50% in children who received dupilumab relative to those who received placebo. We also demonstrated statistically and clinically relevant improvements in lung function and in asthma control scores. So, that all 3 aspects of asthma care exacerbations, lung function, and asthma control were significantly in clinically improved in children receiving dupilumab for a year relative to those receiving placebo.

Dr Teach: Sounds great, Len. It sounds like these agents are making meaningful improvements in asthma outcomes for kids. Can you talk a little bit about your experience, or the experience to date, with these agents around safety concerns and adverse events? Are these biologics safe for children?

Dr Bacharier: Yeah, that's an essential question for all of our patients and particularly our youngest patients. You know, what we've seen now is that there are actually 6 FDA-approved biologics for the management of asthma in adolescents and adults. Three of these are approved down to age 6; 2 of them are approved for 12 and above; and 1 is approved for 18 and older. All of them demonstrate significant reductions in exacerbations. Their impact on lung function is pretty inconsistent. Some show greater improvements than others, and several have been demonstrated to be effective in allowing reduction of chronic oral steroid use -- an uncommon situation in pediatrics -- but we still do see the occasional child who seems to be dependent on oral corticosteroids. When we talk about safety considerations, these are all administered by injection, and therefore, injection-site reactions are a common occurrence but are rarely of significant enough concern to lead patients to discontinue the therapy.

Most patients persist with the therapy and become very used to the injections. Two of the agents, omalizumab and reslizumab, have black box warnings for risk of anaphylaxis. These rates are still well below 1%, but they're not 0, and both recommend availability of injectable epinephrine. Hypersensitivity reactions have been reported with these agents, just like they have with every other pharmacologic agent. There are some unique features. Mepolizumab has an association with the activation of herpes zoster. So, in older patients, we recommend zoster vaccine prior to starting dupilumab. And atopic dermatitis has been associated with conjunctivitis and keratitis and has had some pediatric reports of parasitic infections. So just need to be cognizant of those. Those have all been mild to moderate and easily managed with conventional therapy, nonnecessitating interruption of therapy. So, I think on the whole, based on the safety data we have available, these agents provide very substantial clinical benefit with a very tolerable safety profile. Over time we'll learn a bit more about sort of their long-term safety impacts, but several of these have trials in adults out to 4 to 5 years with no emergence of any new significant safety concerns.

Dr Teach: Thanks, Len. And when you consider these safety concerns in light of what we know about the adverse effects of repeated courses of oral corticosteroids and the implications of uncontrolled disease those obviously need to be balanced. Len, let's go back to the kid we started with. That child was being referred to you as an asthma specialist, having received pretty impressive management by the primary care provider, but that clinician's efforts hadn't achieved asthma control for this kid. So, bring us up to date -- what happened to this child?

Dr Bacharier: Sure. So, we went through our usual stepwise evaluation, evaluating physiology, biomarkers, social determinants of health and barriers to try to understand who this child really was and how we might be able to apply more targeted therapy for him in the future. We did spirometry that showed evidence of significant intrathoracic airflow obstruction. He had a markedly compromised forced expiratory volume in 1 second (FEV1) of 63% predicted. We administered albuterol as a bronchodilator and saw nearly 60% improvement, but still with ongoing evidence of airflow obstruction, we did a comprehensive allergy evaluation that demonstrated that he was sensitized to air allergens, including mold, cockroaches, and mice. We excluded cystic fibrosis with a sweat chloride analysis. We did a high-resolution chest computed tomography (CT) that demonstrated some bronchial thickening and increased anteroposterior (AP) diameter, but no other conditions of concern. We did an airway exam with bronchoscopy and bronchoalveolar lavage (BAL) that showed some inflammation and edema.

We were able to culture Moraxella from the airway and treated him with a course of oral cefdinir, which had no clinical impact. We did biomarker assessment, phenotyping, and found that he had an elevated level of nitric oxide of 36 parts per billion. He had blood eosinophils, a little in excess of a thousand cells per microliter. His IgE was markedly elevated in excess of 4700, and our social work team evaluated him and the family and found evidence of moderate maternal depression and anxiety. So, we had a lot of targets that we could then begin to explore.

Dr Teach: How did you approach choosing one of the biologics?

Dr Bacharier : Before we ever prescribe a biologic, we really want to get a sense as to whether the child is actually using the other medicines that have been prescribed. So, we called the pharmacy. We confirmed that he had received his inhaled corticosteroid (ICS) container controller 10 out of the past 12 months. The family was not in any doubt that he had underlying asthma. They did not have any specific treatment concerns. They were not steroid phobic. They really seemed to understand the disease. We reviewed his inhaler technique because every child has the ability to do this more ways wrong than right. His inhaler technique was really quite good. There were really no reported barriers other than he might miss doses when he spends the weekends with his grandmother, so that was an area of reinforcement. But we really found that most of the social factors and other factors that we could work on were really well addressed and that he really was a candidate for step-up therapy with one of the biologics.

So, we have a variety of treatment choices that we can make for him, and we have to take those in context of features related to the treatment itself. How frequently does it need to be given? What's the route of administration?

What's the safety profile? What's the long-term effectiveness, and what are fear factors that those might elicit in an 8-year-old? We need to think about patient-related factors and their perceived need for additional therapies and need for greater control, and we definitely need to be cognizant of the socioeconomic factors such as the financial burden and the insurance coverage, especially for these agents which are much more expensive than our conventional asthma therapies. Therefore, not discounting any of these is a recipe for poor adherence and suboptimal outcomes.

Dr Teach: All of this of course, Len, needs to be done in conjunction with the family, and I'll just briefly stress the importance of shared decision-making. There's an interesting tool available actually from the CHEST Foundation which really moves that discussion forward. It identifies patient preferences and values. The clinician really provides the patient biomarkers, and then the result is a personalized option for the family. What is a strategy for choosing a biologic for children 6 to 11 years of age with moderate to severe disease uncontrolled by stepwise therapy?

Dr Bacharier: Sure. We have an 8-year-old child in front of us, so we can exclude all of the agents that don't apply to an 8-year-old. That leaves us with 3 [agents]: omalizumab, mepolizumab, and dupilumab. We do our biomarker characterization. First, we ask, 'does the child have evidence of allergic asthma?,' and it's clear that allergic asthma does not necessarily pigeonhole a child into one of these therapies. While omalizumab targets IgE, there is compelling evidence that both mepolizumab and dupilumab -- as long as there's evidence of eosinophilic or type 2 inflammation -- work well in children who have allergic disease. So, allergic asthma really isn't a great deciding factor between these because they can all work. We look at peripheral blood eosinophil counts, and once your eosinophil count is in excess of 150/μL, there is clear evidence that dupilumab and mepolizumab are effective in those patients. If eosinophil counts are over about 200/μL, there is evidence that omalizumab is also likely to be effective. None of these are effective in patients who have low levels of nitric oxide. So, the cutoff is usually 20 to 25 parts per billion (ppb). Since our patient's NO level was elevated, there's evidence that omalizumab and dupilumab are likely to be effective in such patients. We also look for comorbidities, and recall that this child has a history of moderate atopic dermatitis. Dupilumab carries an indication and is demonstrated to be effective in reducing the severity and morbidity associated with atopic dermatitis. So, in a patient who has moderate to severe atopic dermatitis, along with evidence of type 2 asthma, dupilumab might have an advantage in its ability to treat multiple conditions simultaneously. So here, if we look at how our individual patient, age 8 with allergic rhinitis, atopic dermatitis, and eosinophil count of over a thousand, a FeNO of 36 ppb, and an IgE level of 4700 IU/mL would stand to benefit from these therapies. We see that the most highlighted areas of agents that are most likely to be effective, really lead us to mepolizumab or dupilumab. His IgE is just too high for omalizumab therapy, and given his elevated FeNO and his concomitant atopic dermatitis, it seems like his greatest likelihood of response would be with therapy related to dupilumab.

Dr Teach: I love to hear you walk through that decision-making process. It was extremely clear, and I'm really curious, what was the next chapter in this child's story?

Dr Bacharier: Sure. So, we went through the full shared-decision-making process. The family was on board with a step up in care based on our collective assessment of the risks and benefits. We recommended and the family took us up on a trial of dupilumab 200 mg injected subcutaneously every 2 weeks. We initiated home visits that led to remediations related to cockroach and mold exposures. We helped mother get some counseling related to her depression and anxiety. We had an ear, nose, and throat (ENT) evaluation that thought that his sleep apnea was substantial enough to warrant an adenotonsillectomy, which was safely and completely performed. Then we followed him for the next 6 months and beyond, and over that 6 months, there was a transformation that the family was delighted in. We had no exacerbations or school absences. His albuterol use went from daily to infrequent. He became a fully engaged participant in all the physical activities that he wanted to enjoy. His status improved, including his atopic dermatitis. I think this isn't the average response; this is really a quite excellent response. But I think using this multidimensional strategy with the addition of the biologic, we really substantially improved this child's asthma course, care, and quality of life.

Dr Teach: Well, thanks, Len. It's great to hear that child is doing so well. His experience really resonates with my experience in the application of biologics in children with disease that has been uncontrolled by stepwise therapy. Well, Len, this has been fun. Thank you very much. It's been great to have this discussion with you.

Dr Bacharier: Yeah, I very much enjoyed it. I hope this has been a clinically relevant discussion for our audience and that these points help folks put these newer agents and strategies into perspective and encourage folks to help their patients get the care that they need so that their asthma does not get in their way and that they can have full and productive lives. So, thanks again.

This transcript has not been copyedited.

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