Dr. Gerry Lee (Host): Hello, everyone, and welcome to another episode of Allergy Talk, a roundup of the latest in the field of Allergy and Immunology by the American College of Allergy, Asthma and Immunology. For today's episode, we'll be reviewing some more articles from Allergy Watch, a bi-monthly publication, which provides research summaries to college members from the major journals in Allergy and Immunology.

And by listening to this podcast, you can earn CME credit. For information about CME credit, head over to education.acaai.org/allergytalk. And we also continue the conversation on the Doc Matter ACAAI community. So definitely join in the conversation.

Well, nice to talk to everyone again. My name is Gerry Lee. I'm an Associate Professor at Emory University. I'm also an Assistant Editor of Allergy Watch. And today, once again, I'm joined by the Editor-in-Chief of Allergy Watch, Dr. Stan Fineman.

Dr. Stan Fineman: Thanks, Gerry. It's great to be here. And I'm the past president of the college. And as Gerry said, Editor-in-Chief of Allergy Watch. I'm on the adjunct faculty at Emory as well.

Host: And for the third chair, we're excited to be once again joined by Dr. Sarah Spriet, a staff Allergist Immunologist at A.T. Augusta Military Medical Center and Associate Program Director for the A/I fellowship at Walter Reed and an Associate Professor of Pediatrics at Uniformed Services University. She's an Assistant Editor of Allergy Watch. And again, we're excited to bring her back. Sarah, welcome back.

Dr. Sarah Spriet: Hi, gentlemen. Good to be with you.

Host: All right. Well, we sort of have an asthma theme to this episode. So, let's start with the basics. Dr. Spriet, sounds like there's something that's just low-hanging fruit that could help all our asthma patients

Dr. Sarah Spriet: Well, that's right, Gerry. Exercise fixes everything. And if you're like me, you often will prescribe exercise to your asthmatic patients. And I really like this article because it brings some granularity to that prescription. I haven't up until now had specifics to tell my patients about how long should they be exercising and at what intensity.

And so, Dr. Valkenborghs and colleagues based out of Australia published this study and the title is Effects of Moderate versus Vigorous-Intensity Exercise Training on Asthma Outcomes in Adults. Essentially, the title tells you the aim of the study. In short, this was a perspective 12-week randomized controlled trial with 46 asthmatic adults. The subjects were randomized to one of three groups. The first treatment group was a moderate intensity exercise group. They performed 45 minutes of moderate intensity exercise, which was determined by 55-70% of their age-appropriate max heart rate three times a week, whereas the vigorous treatment group performed vigorous training assessed at 70-90% of their max heart rate for 30 minutes three times a week or the control group.

And this was a 12-week study, as I said, so only three months long. And at pre and post intervention, the researchers assessed the participants' asthma-related quality of life questionnaire score, their asthma control score, their cardio-respiratory fitness measures to include VO2 max, their body composition and markers of airway and systemic inflammation. Most of these participants were female, and the mean age was 39 years old. And so, what they found is that both intervention groups' quality of life, and their asthma control questionnaire scores significantly improved following the intervention. They did find that vigorous training was associated with improved cardiorespiratory fitness measures. And that moderate training was associated with reduced sputum macrophage and lymphocyte counts. And they did find some reduction in total body mass in the treatment groups. Those who had reduction in their android fat mass, that was associated with reductions in sputum IL-6.

And so, I think the main takeaways from this small study was that they did find improvements, particularly in those symptom and control scores. And while it was limited in sample size, this prospective data does give us some clarity when we're prescribing exercise to our patients. And really bottom line up front, both of the treatment groups improved. So if your patient has a preference of moderate versus vigorous training, they should do whichever they prefer. And both are better than the control.

Dr. Stan Fineman: This was very interesting to me. I've tried to recommend exercise to my patients with asthma as well. The baseline characteristics of most of these patients you mentioned were female. But can you comment on were they overweight or, I mean, did they tend to have healthy lifestyles before or what do you think about that?

Dr. Sarah Spriet: At least in the baseline characteristics table, I get the sense that at least in terms of total lean mass, they were similar in all of the groups, but I didn't get a good sense of what their baseline exercise frequency or intensity was coming to this, aside from those baseline VO2 measures that they performed on treadmill and cycle at the one point in time prior to the intervention.

Host: Sarah, I think this is something that we know we should all be doing a better job with. A lot of the visits go, "You got asthma. Here's the medicine," and we're going to call it a day. And allergists, we take this extra effort, we're going to look at exposures, we're going to do testing and help with avoidance. I'm not saying that we're just going to throw medicine at it, but there's just so many things we could be doing to help asthma. And definitely, physical activity, it is essential. I mean, clearly, it is a lung disease where deconditioning can occur and absolutely improving. That shows obvious benefits, but I think a big barrier is how to do it.

So, you mentioned you love doing the prescription. I would love advice from you, what do you think is your approach to prescribing activity? I'd love to hear your thoughts.

Dr. Sarah Spriet: Well, and up until I had this study, I had really leaned on more general speaking to educating, "Hey, you have a chronic lung condition and we anticipate your function is going to naturally decline with age. And if it's uncontrolled, that function is going to decline faster. And so, I strongly encourage in more general terms, get out there, be more active to optimize the function that you currently have.

And I've encouraged them to start with a walking program if they don't currently have any structured exercise program, and I've pointed them to some that start slowly and gradually increase. But now, I feel more comfortable speaking to, "Hey, here are some actual parameters for heart rate and frequency of exercise. Let's aim for 30 minutes even to start of moderate and build up to the 45 minutes of moderate three times a week." So, I feel like this gives me a little more clarity to speak in more specifics to my patients.

Host: You know, you almost want to put it in the green zone of your asthma action plan. You know, like, this you should be doing all the time. Just throw that into the green zone. You know what I mean?

Dr. Sarah Spriet: When feeling well, aim for this level of heart rate and frequency and intensity. Exactly.

Dr. Stan Fineman: And everybody's looking for a more holistic way to approach these chronic illnesses and the fact that patients can just go for a walk and help their asthma. And also, we have data now. It's always nice when I approach the patients is to be able to say, "There was this study that showed you walk for 30 minutes, you know, that it's going to help you."

Host: And I also want to mention the group of individuals who avoid asthma triggers, right? They avoid physical activity because it's an asthma trigger or, "My kid keeps on running around, it's making his asthma worse. I'm trying to rein them in." And if we could sort of explain why physical activity is beneficial and then we're going to remove the barriers by controlling their asthma with medicine to facilitate improvement of physical activity. I think we can all get on board with that and then sort of address some of those concerns too.

Dr. Sarah Spriet: Absolutely.

Host: Okay. Well, thanks for that reminder. I think we should all be doing it. I'm going to say that if you're asking me have I prescribed it every single patient, I will absolutely do that and change practice, because I don't think I've done it. I'm not betting a hundred percent on that. I know I should be.

But I'm going to switch to something that really surprised me. So, I'm really actually excited to talk about this article. So this was in the Blue Journal, and the title of the article is Human Neutrophils Coupled Nitric Oxide Production and Extracellular Trap Formation and Allergic Asthma. And this was reviewed by Tim Chow in the latest Allergy Watch issue. So, nitric oxide, we often are very concerned about elevated nitric oxide. We think of T2 inflammation. The guidelines state elevated nitric oxide is one of the tools we use to determine if someone's having active T2 inflammation. And T2 conjures a lot of thoughts, right? It conjures eosinophils and that sort of thing.

And so, I found some interesting things about where nitric oxide comes from. I may have learned this in fellowship. I'm telling you, I have only certain capacity in the brain and certain things leak out. But anyways, a reminder for all, the traditional mechanism of nitric oxide production is you have this amino acid L-arginine that gets transformed by NOS or nitric oxide synthase to nitric oxide. And there's constitutive enzyme. There's inducible NOS that comes from inflammation. But what I didn't know, and this was like way new knowledge for me, cytochrome P450, or just straight up reaction of oxidant species like peroxide, can catalyze the same reaction without NOS. NOS is not the only way you make nitric oxide. And so, I mentioned hydrogen peroxide. That's going to invoke some thoughts about neutrophils. So neutrophils, as you know, create hydrogen peroxide, right? NADPH oxidase during the oxidative burst is going to make reactive oxygen species. And so, that's one line of evidence.

Another thing that they thought was interesting that inhibiting nitric oxide doesn't eliminate nitric oxide. So clearly, experimentally, we've proven NOS is not the only source of nitric oxide. And there is some preliminary evidence that nitric oxide can activate neutrophils to do a defense mechanism called a NET or neutrophil extracellular traps. And for those of you who don't recall this, neutrophils have this ability to basically explode. They just basically barf out their DNA. And it's like this sticky, gooey substance that traps bacteria and other pathogens and is an inflammatory as well.

So, they saw there's some purity evidence that maybe there's more to the story of nitric oxide and asthma. So, this is a Spanish study that enrolled 99 patients with allergic asthma, and they had this control group that basically had no allergies whatsoever, like healthy individuals. And they were able to get peripheral blood and then some of the patients got to do sputum. And they had this isolation technique where they can isolate each type of cell. So, they have this technique where they can get neutrophil purity of over 99% purity, like 0.001% was eos, I'm not going to say there's no eos in there. And they wanted to examine what happened in these allergic patients if you did allergen challenge. And wouldn't you know it? If you expose purified neutrophils from the peripheral blood of individuals of allergic asthmatics, they release nitric oxide. And I didn't say mast cell. We're talking, it came from the neutrophil. And if they're not allergic to the allergen or they're non-allergic in general, this did not happen. It was absolutely Ig-mediated dependent. They actually blocked ______ receptor and you don't see it. All right.

So through an Ig-mediated mechanism and allergic asthma, neutrophils, neutrophils are making nitric oxide. And so, they really wanted to explore this further, and they found that it does involve NADPH oxidase, right? It doesn't involve NOS. Again, as that earlier study I told you showed that they actually can activate neutrophils. You expose neutrophils to NO, they will do that; again, net formation and, again, explode and barf out their DNA.

Well, they looked at eos, right? So, they got eos, nothing. The eos did not release nitric oxide. I know. So, boy, I learned a lot. That was very unexpected. I mean, people are just drilling into my head. T2, T2, T2. Eos, eos, eos. And we had this study that's showing this maybe underappreciated role of neutrophils contributing to asthma through this mechanism of nitric oxide. And I think I really just have to now go back to the drawing board, re-teaching myself about what's really happening in the airway when we're having allergen or Ig-driven allergic response, right? Because neutrophils are probably contributing as much as mast cells or other epithelial cells in the pathophysiology of asthma. And therefore, we sort of have to think about therapeutics, how are we going to go after this, and maybe interpreting nitric oxide correctly. Because there are definitely patients who have elevated NO, but you're not seeing these other signs. So, you're asking, where's that coming from? And maybe that's where it's coming from. I thought it was very interesting.

Dr. Stan Fineman: Gerry, you're right. I mean, I used to do a lot of exhaled nitric oxide on our asthmatic patients that we were seeing in practice. And many times, there was this disconnect. And, I mean, it's a very complicated study. And I think it's a new concept, but I'm going to make a plug for Allergy Watch because this is in the journal, the American Journal of Respiratory Disease and Critical Care Medicine, which is not on my normal radar screen. So, the fact that Tim Chow made sure we were aware of this, I think, is very important. And just you're right, as you said, you learned a lot. I think, I learned a lot. Everybody will too.

Host: Okay. Well, Stan, it looks like we got one more article to go. And I think that anything from Gerry Teague is extremely interesting, but it looks like he's unpacking the mystery of treatment refractory wheeze in toddlers. Tell us about this one.

Dr. Stan Fineman: So, this was a study that was published in September 2024 in the Journal of Allergy Clinical and Immunology by Gerry and his group from Virginia entitled The Novel Syndrome of Silent Rhinovirus-Associated Bronchoalveolitis in Children with Recurrent Wheeze. And the thing that piqued my interest in this study is that this was a study of children who went through a bronchoalveolar lavage. They basically all had a bronchoscopy because they had persistent wheezing that was not controlled. And what they were able to find. They did a variety of studies on the BAL fluids and, particularly looking at their cells and looking at the bacteria cultures, lymphocyte counts, T2 inflammatory markers. And they were also able to use molecular methods to, you know, identify certain other pathogens, such as viruses that we now identify that way.

And the thing that's of interest in this study was that the children who had recurrent wheezing, often had what they described as a new silent syndrome of lung rhinovirus infection. And the reason they said that is because they found the rhinovirus in a substantial number of patients. So, 30% of the children who had refractory wheeze did have a positive test for rhinovirus, which is extremely high. And the other thing that they found was that these children, a number of them had very high neutrophils in their bronchoalveolar lavage.

And this is kind of in contrast to what we see when we do nasal swabs. When communities do nasal swabs in patients who have wheezing to detect rhinovirus, even asymptomatic children, 35% can have rhinovirus in their nose when they do, nasal secretions. But this was the first study that did bronchoscopy in these children. And they found pretty similar, about 30% these children as well. As you know, I mean, Gerry, you were the one who this to the attention of Allergy Watch. And in your comment on the paper, it stated that the author suggest caution in escalating inhaled corticosteroids for patients with refractory wheeze, given the potential suppression of antiviral immunity, which is something we need to keep in our mind. We always try to push more and more steroids and that may not be the best thing for these patients.

The other thing I didn't mention that I do want to bring up is the fact that of the children who did have these positive rhinoviruses, they tend to be younger. And they also tended to have the higher dose steroids, and they did tend to have the higher neutrophil counts. So, eosinophilia was a little bit higher than the ones who didn't have the rhinovirus, but it wasn't 10 times fold as it was for neutrophils in the children who had rhinovirus in their secretions as well.

So, maybe this is a new "silent" rhinovirus infection, because we weren't aware of it and trigger these persistent wheezing patients. But I think that, as you said, Gerry and his group from Virginia, it's good that they bring this to our attention, because we don't do very many bronchoscopes on our wheezing infants. And so, it's interesting to see what's going on in their lungs.

Dr. Sarah Spriet: I totally agree. I think informative adds to our body of knowledge. I'm not sure if it changes my practice other than the point that you made of reigning back on the steroid prescription if I am engaged or involved in one of these patient's care.

Host: You know, we always think about then what's the alternative, right? I'm on board if you're just escalating inhaled oral corticosteroids, and the patient is not getting better with the wheezing, clearly this is not a steroid responsive condition and continuous infection, maybe latent infection. I would imagine immune suppression could worsen that. So, did Dr. Teague talk about alternative approaches for this type of patient, Dr. Fineman?

Dr. Stan Fineman: Well, he didn't specifically comment on some of the alternatives in this particular paper, but he's written other papers and he's spoken before about that. And you might want to comment about the fact that when he came to Emory, he presented the Grand Rounds.

Host: I mean, I was teeing you up, Dr. Fineman. But yeah, I think one of the things we've seen for this non-T2 type of asthma, if people have trialed azithromycin, there are patients where especially if their negative modified asthma predictive index, they don't have the high eos or the eczema or allergies. Sometimes, and this has been trialed before, those wheezing infections treated with azithro prevents an exacerbation. I think that was trialed earlier, like in the April study and so on. So if we were going to try to phenotype and identify these children early, maybe infectious wheezers, especially negative modified as predictive, instead of more inhaled steroid during illness, our usual strategy may be azithro, especially as a trial to see did that move the needle? It could be something we could consider. I know for refractory asthma, there's a significant reduction in exacerbations, and I would imagine that's not helping everybody. It's probably unmasking a subgroup where our current treatments like inhalers, and they're reaching stuff by therapy is not working. And I think this is the group. I think this is maybe, again, very speculative.

So anyways, those were awesome articles. I learned a lot, and I continue to have more ideas in how we're going to help these patients. If you like what you heard and you have any questions or maybe you have an experience that could contribute to this discussion, please email us. The email is allergytalk-- one word-- @acai.org. And don't forget about that CME credit. You just go to our website. It's education.acaai.org/allergytalk, where also on the college website, you can read those archive issues if you missed a previous issue. That's college.acaai.org/publication/allergywatch. Well, I always find this fun. Thanks for listening, and we'll catch you next time. Have a wonderful day.

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