All right. We'll move into the Grand Rounds portion of the day. And we're very excited. It's an honor for us to have Dr. Larry Borish here today from the division of Allergy and Immunology. Dr. Borish is a professor of Medicine and Microbiology, and holds appointments in a number of groups of institutions. So both the Asthma and Allergic Disease Center, the Cancer Center, and the Carter Immunology Center. And in terms of some brief background, Dr. Borish started his education and training in Boston at Harvard College before moving on to Boston University School of Medicine, and then internship, residency, and fellowship through the Harvard and Tufts Medical systems. And over the years, Dr. Borish has developed an expertise in a number of areas, including severe asthma, chronic sinusitis, and adult immunodeficiencies. He's also been a pioneering researcher in the field studying the immune and molecular mechanisms inherent to upper and lower airway allergic inflammation, and has become kind of a national leader in the field, serving on the editorial board for the Journal of Allergy and Clinical Immunology and the associate editor of the American Journal of Rhinology and Allergy. He has lastly been recently elected to the board of directors for the American Board of Allergy and Immunology. So today, with all that background, we're very fortunate to have him here to speak to us about the intricacies of asthma and that spectrum of disease, and how we can better characterize and treat that disease or spectrum diseases. So with that, please join me in welcoming Dr. Borish. Thank you. [APPLAUSE] So first of all, Tom, can you hear me? I was about to say, this is the first time he's ever listened to me, but he's not even listening to me now. [LAUGHTER] Let me begin with a shameless plug for the brand new clinic that I'm starting with Drew Harris. Drew has clinicals happening, which is why he's not here. But we're going to be doing a joint severe asthma clinic starting next week, where we will see patients together. Now, that's his local pulmonary allergy collaborative clinic. I really wanted it to be the clinical respiratory asthma pulmonary [INAUDIBLE]-- some of you have worked it out-- clinic. But I got vetoed on that one. So we're doing exactly what the NIH guidelines say, and our patient isn't getting better. I will be talking about products by those pharmaceutical companies. So you will judge my honesty. And those will be obvious. So this is what I'm not going to talk about when a person is failing treatment. Possibly the most common issue is going to be it's just not asthma. One of my quips is, in America, if the batteries on your remote control die, and you have to get off the sofa to change the channel, and you are short of breath doing that, somebody will diagnose you with asthma and give you an ADVAIR prescription. Lots of causes of shortness of breath. Now, a lot of my fellows, and fellow faculty, and colleagues are here. They understand this. For the rest of you, I don't have time to go through this, but in the world of asthma we have this incredibly distinct phenomenon, which is that sometimes our patients don't do exactly what we tell them to. I can explain it to the rest of you later. So here's what the NAEP guidelines tell us. A patient has symptoms consistent with asthma. If the symptoms occur more than once or twice a week, then start the patients on inhaled steroids. Because we assume that he or she has a steroid responsive disease, and the patients will do exactly what we tell them, and therefore everyone will get better. Or do they? So I'm going to go through each of these bullet points as part of the talk, starting with the question, exactly, what is asthma? When I came here 20 years ago, I had the arrogance to give you an answer to that question. I knew exactly what asthma was. But it's been about two decades since I could actually give an intelligent answer. My naive, 20th century definition was, someone who was allergic, has reversible airflow obstruction, has this type 2-- I'm going to talk a lot about these three horsemen of the asthma apocalypse, IL4, IL5, and IL13-- inflammation, with eosinophilic infiltration of the airway. Now, the problem, of course, is only about half the patients are allergic. The airflow is often irreversible. They come in, they're obstructed, you give them a bronchodilator, it doesn't get better. What disease is that? It can be type 2, but it can be type 1, interferon gamma. It could be interleukin 17. It can be both. It could be neither. And is it really always eosinophilic? So with that, let me introduce the concept that, like a lot of conditions, we're all dealing with, endotypes. Asthma is a waste basket of lots of distinct diseases, and I'll start with the most problematic one. The absolute, categorical definition of asthma always was eosinophilic inflammation, except that a lot of it is non-eosinophilic. I am fortunate, here at UVA, to have as a dear friend and colleague, Jerry Teague, who works as the head of pulmonary and pediatric pulmonary. And over the past decade or so, as part of the clinical care for its severe children and adolescents with asthma who are uncontrolled, many of them have had a brnchoscopy. And this study is a summary of the data we've collected on 189 children who have undergone a brnchoscopic examination for treatment-resistant asthma. And one of the things we do with that tissue is collect the bronchoalveolar lavage fluid and look for the presence of neutrophils or eosinophils. And this is based on lots of validated criteria on what constitutes higher numbers of eosinophils or neutrophils compared to what healthy people have. So eosinophilic lung disease in severe asthmatic children, exactly 8.5%, neutrophilic inflammation, 24.3%. mixed 22.2%. Neither neutrophils nor eosinophils, almost half of them. If you add up the two eosinophilic categories, that comes out about 30% of severe asthmatics have eosinophils it in their airway. So at UVA we use a 30% number. This is a study from UCSF. I think it's the best asthma study done, and the most intriguing asthma study done in the past decade. They do a bronchoscopic exam on that many people-- 50 volunteers. They did proteomics to identify all the proteins present. They do unbiased cluster analysis, and asked the question, what type of inflammation is present? So they determine that Th2-high-- that's the high IL5 and IL13 group-- that works out to about 28 of those 50 asthmatic subjects. And those are the red bars there that are clearly elevated. 22-- again, almost half of the subjects-- don't have a Th2 disease. Their IL5 and IL13 levels look no different from the people in the gray bars, the healthy controls. So that's the UCSF, Virginia. New Zealand-- in this study, they used induced sputum. Everybody came in on inhaled steroids. They took away the inhaled steroids. And either for a month without steroids or until they lost their asthma control, at which time they did an induced sputum exam, and again look for eosinophilic disease or non-eosinophilic disease. Their numbers-- eosinophilic, 60, non-eosinophilic 28. So again, one third of patients don't have an eosinophilic disease. So what is this disease that doesn't have he eosinophils and largely has neutrophilic disease? Part of this, of course, is a steroid phenomenon. Steroids do the opposite to neutrophils, as they do to eosinophils. Meaning, steroids actually inhibit neutrophils apoptosis. In the presence of steroids, neutrophils survive a very long time. So paradoxically, if you have a neutrophilic process, it is going to get worse if you give them oral or systemic or topical steroids. So some of this is just a steroid effect. Some of it is the fact that these patients have a non-Th2 inflammatory process. I'll show you those data in a second. So some of these people have high interferon gamma, Th1, or Th17-- IL17-- cytokines that are critically important for neutrophil recruitment and activation. So this is one of the earlier studies that shows in a log scale on the bottom how much IL17 RNA is in the lung and percent of neutrophils in the airway. And you get a pretty good linear relationship, whether or not the patient's on a health series are not, between the amount of IL17 and the percent of neutrophils. This is our study with Jerry Teague, again, looking at interferon gamma, the Th1 cytokine. And again, for human research, an r of 0.52 is actually pretty good. And again, a log scale, looking at interferon gamma concentrations in the y-axis, and the neutrophils counts on the x-axis. The more inteferon gamma, the more neutrophils. And we saw similar results with GCSF and IL17 in our study. Why do you care? Because the NAEPP-- that is the NIH guidelines-- tell you that every asthmatic should be on inhaled steroids. But I just told you, steroids don't work if you have a neutrophilic process. They will actually preserve the neutrophils, keep them surviving, for weeks, if not longer, and exacerbate the inflammation. So we go back to the UCSF study shown here. These are patients not on inhaled steroids who had their bronchoscopy, got categorized as Th2-high or Th2-low. To Th2-high folks are in the red. You put them on Fluticason. And those are the data that drive the NIH guidelines. Everybody's lung function gets better quickly, and for weeks, almost half a liter improvement in FEV 1. A third of those patients, you will recall, were Th2-low. They're in blue. I don't know if that's statistically significant worsening, but nobody will argue that none of those patients are getting better. And you can do a study of 100 asthmatics, or 1,000-- basically, all the studies on inhaled steroids done by the FDA-- and if two thirds of the patients are getting a lot better, you can get a really good p value that steroids work well. But fully one third of our patients, at best, are not getting better, and may be getting worse with the inhaled steroid. Now, this is that New Zealand study I showed you earlier. I'll just highlight the second row down, That's the lung function when they got put back on inhaled steroids. If you had eosinophilic disease, 80% of them get better. Steroids work great for most people with eosinophilic asthma. In the presence of steroids, neutrophils live forever. As I like to quip, an eosinophil will not survive in the same continent where somebody has a molecule of cortisone around. They really hate the stuff. But if you have non-eosinophilic disease, 14% got better. Fairly astounding numbers. Now, those studies-- every study I've done, it was in the last decade. A complete reawakening of how we think about this disease. Steroids can be ineffective or bad in our patients. Except, of course, that there is nothing new under the sun. This is 1958. That's the title of the paper that appeared in Lancet in 1958, where they knew back then that you could get an induced sputum sample, and if there was eosinophils present, the patients got better on prednisolone. And if there were no eosinophils present, the prednisolone systemically had no benefit whatsoever. So this has been known for 60 years, but only recently rediscovered. So a third of our patients have a neutrophilic disease. How do we treat them? Macrolide antibiotics, perhaps. This is clarithromycin twice a day. There's some data to support that, either because of its anti-inflammatory effects off-target, or maybe because this is a chronic microplastic disease. Nobody knows why they work-- magic happens. Methotrexate has been tried. It's a pretty effective anti-neutrophil agent. The old standby that should never have been taken off the market, at least for these patients-- it always worked. It did have a narrow therapeutic window, but it does work. The modern era, we have the expensive version of theophylline. With the same safety issue, not approved in asthma, but the PDE4 antagonists like roflumilast could work. The real bottom line is this is a huge, unmet need. And it's a big area of research at the NIH, because we really don't know what to do with these patients. And they may be 30% of all asthmatics, but they make up a huge percent of the people we're seeing in a severe asthma referral center. So I mentioned earlier that this is largely an IL17-driven disease. So that raises the question, why not try an anti-IL17 agent? So I gave this slide the title, How NOT to design a clinical trial of a biologic in asthma. So the drug was brodalimumab which is being used in IL17 disorders like psoriasis and so forth. And it's an anti-IL17 receptor, so it blocks the binding of IL17 and its biological effect. Their subjects were inadequately controlled, moderate to severe asthma, despite being on high dose inhaled steroids. No attempt was made to identify whether any of these patients actually had IL17 in their airway. They didn't get bronchoscopy, they didn't get sputum. We don't even know if they had a neutrophilic disease. And that slide is completely blurred out-- nobody can read it-- but three of those are the drug. One of them is the placebo. And from the back of the room you can see absolutely no benefit whatsoever. Which is a tragedy, because there are asthmatics with an IL17-high disease. And if we can figure out how to identify them, this would have been the right drug. So let me move on to a couple other asthma phenotypes, starting in the eosinophilic category with those who actually have an allergen exacerbated presentation or who are eosinophilic. So allergen-exacerbated asthma-- the immunology, this is the quintessential Th2-high disease. High levels of IL4 and IL13. I'm going to talk a lot about them later, the cytokines that drive IgE production, the allergic isotype. And IL5, the eosinophilic poietin. So the definition is, these patients have to have allergies. If you do an immunoassay or you do a prick test, they have evidence of allergy. But it's not just that. And this is a huge problem, because the joke I like to give is, what percentage of patients with nonallergic asthma have positive skin tests? Now, you got that? Nonallergic asthma, positive skin tests. So the way I work people through this is, what percentage of people have allergic appendicitis? Most of you don't know this, but we run an incredibly busy consult service in the allergy [INAUDIBLE] division. If somebody enters the emergency room, they have a right-lower quadrant pain, rebound, fever, they immediately call the allergist on-call to be skin-tested. Because if the skin tests are positive, we can diagnose them with allergic appendicitis. What percentage of people at UVA, coming to the emergency room, have allergic appendicitis? 50%. Correct. Now, that was a joke. There's no such thing as allergic appendicitis. [LAUGHTER] What percentage of people with nonallergic asthma have positive skin tests? Same. 50%. You can't use skin tests to diagnose allergies. You have to diagnose a history, meaning that the person has some medical history that allergen exposure causes lower and upper airway symptoms, and they're being actually exposed to the allergens to which that's driving those symptoms. An important diagnosis to make, because we have treatments for these people. We can have them avoid their allergen. We can start them on allergy immunotherapy. Or we now have a new drug, omalizumab, which is anti-IgE. These are the clinical trial I would have sold my soul to take in part of, bad asthmatics who volunteered to spend 16 weeks in the Swiss Alps to see what would happen to their asthma. You go high enough in the Swiss Alps, you have an environment where there are no dust mites because it's too dry, no mold because it's too dry, no pollinating plants because they don't grow that high. And you had to spend four months up there. They couldn't pay me enough. And this is what happened to their lung function. FEV1s are looking pretty good. Lung function goes from 77% to 122%. But look at the PC20. That's the twitchiness of the airway-- the reactivity to methacholine. Pretty much no change. They do sputum eosinophils before and after, pretty much no train. So these studies show great improvement in lung function, quality of life, rescue albuterol use, but the twitchy airways are still there, the inflammation is still there. The implication-- allergens exacerbate asthma. That's my preferred term allergen-exacerbated asthma, not allergic asthma. And I've put this in red, because I'm you're going to be seeing a lot of this in the last part of the talk, allergens have little to do with the day-to-day asthma symptoms or the severity of the disease. So this is one of our newer drugs for asthma, anti-IgE. So you all appreciate the importance of IgE. This medication basically eliminates the ability of IgE to mediate its nefarious effects. And the FDA approved the drug based upon these data, which was a reduction of exacerbation rate. So these are severe as medics who were having 2, 3, 4 exacerbations of their asthma a year-- the people you all know who are frequent flyers in the emergency room or in the hospital. And what you're seeing here is about a 50% reduction in exacerbation rate. And this was the first time the FDA approved a drug based purely on that outcome measure and not other measures of asthma. Which is a good thing, because it did pretty much nothing to lung function symptoms, severity, rescue albuterol use. And again, I'll look at that and say, the implication is that allergens have a lot to do with asthma exacerbations-- thus my calling it allergen-exacerbated asthma-- but not a lot to do with day-to-day asthma symptoms or severity. Now, I love these pharmaceutical trials. And I love taking part in them and doing the basic research. I am not a mouse biologist for an obvious reason. I spent the summer of-- it was during the Harding administration, at Jackson labs, and it's the closest I ever came to dying from asthma. I can't do mouse research. But I've always been jealous of my colleagues who can do mouse research, because they can do wonderful things like generate conditional mouse knockouts. So you can take a mouse, give it asthma, conditionally knock out the IgE gene, and then sort of dissect out what IgE is doing. But thanks to the pharmaceutical, we actually get to do these kinds of studies where we could make conditional human knockouts. Meaning, give a person anti-IgE and define what is the role of IgE or IL4 or IL5-- things I'm going to talk to for the last few minutes of this talk in this disorder. And the implication is that a human conditional IgE knockout still has asthma, still has hyperactivity, still has day-to-day symptoms, the exacerbations go away. So the last phenotype I'll talk about is the eosinophilic disease. So this is a disease where the immunology is, they may or may not have an allergic component. Child, adolescent asthma, almost always allergic. People think of this as a child-onset disease, but as everybody in this room knows, the prevalence of asthma, the incidence of asthma, actually peaks again in adulthood. And when you look at the h onset asthma, those tend to be the patients we see with the highest levels of eosinophils. Very rarely are those patients allergic. So you have eosinophilic process without the IgE process. And for lots of reasons, that looks like an IL5 disease. IL5 eosinophilic poietin acting without IL4, the cytokine driving IgE production. So loss of eosinophilic airway. Therapeutic implications-- I already told you what the big one is. This is what's driving the NIH guidelines. These are people who will get better on steroids, because an eosinophil cannot survive in the same continent where there's a molecule of cortisol. The problem, of course, is this phenomena of steroid-resistant. Because that's the other big component of the patients we see who indeed are being compliant, have [INAUDIBLE] disease. They're still in emergency room or in our clinics. The steroids stopped working. Steroid-resistance is another hour lecture, but the phenomenon of sterioid-resistance, which is so disturbing, is that eosinophils lose their ability to die when they see steroids, but you don't lose the ability to have all the side effects. So these are the patients who are getting the osteoporosis, and the Cushing changes, and every other side effect. They're just not getting any relief of their asthma, despite being on inhaled or oral steroids. And for them, we have these eosinophilic targeting biologics. So these were the two early studies from a decade ago that really pointed to the fact that if you give somebody anti-IL5, a drug that will shut down eosinophil poiesis, you can prevent asthma exacerbations. So two studies, same issue the New England Journal, and they learn from the anti-IgE studies to look at exacerbation rate. So on the left, what you see is the placebo patients in the severe, high exacerbation cohort. 80% had an exacerbation by about 24 weeks with mepolizumab, anti-L5, only about 20% exacerbate. In the study on the right, you see about a 50% reduction. So as with omalizumab, these drugs prevent about half of exacerbations. Now, these were severe asthmatics. In order to go into the study, they have to have eosinophils in their sputum. High-dose steroids, there's still eosinophils. Steroid-resistant, and, obviously, it's not the neutrophilic disease. And what's also remarkable is, these were the best data. No real improvement in FEV1 control symptoms albuterol use. What is the implication? That IL5 is primarily important in driving exacerbations. So this is a similar antibody. It came out a year or so after the mepolizumab. This is now anti-L5 receptor, benralizumab. So it'll do the same thing. In this case, it'll block the ability of IL5 to bind to its receptor. And the data on the left are the exacerbation rate data, showing that, at two different dosing regimens, about a 36%, 30% reduction in exacerbation rate. In this study, there was a modest improvement in lung function. But still, the major outcome is reduction in exacerbation rate. So again, anti-IL5 or anti-IL5 receptor, they improve, they don't eliminate asthma. The best outcome is prevention of exacerbations. Not much influence, as I just said, on lung function, symptoms, severity, rescue drug use, whatever. Implication-- IL5 eosinophils may drive exacerbations. They seem to not have a lot to do with day-to-day asthma symptoms or severity. So again, this is the pharmaceutical allowing people like me to study conditional human IL5 knockouts. It's not what causes the disease. It's responsible for the exacerbations. So the other two cytokines of the type 2 disease apocalypse are IL4 and IL13. I'm not going to go through this whole slide. The reason why IL4 and IL13 initially invited blockade is because those are the cytokines, the bottom, at about 4 o'clock, that are driving B-cells to make the isotype switch to IgE. If there's no IL4, IL13, you don't make any IgE antibodies. If you block it, the IgE antibodies you have will eventually go away. But they do a lot of other really interesting things. They don't drive eosinophil poiesis. They make it possible for those eosinophils to get out of the circulation and into the lung. So they act on endothelial cells to drive the adhesion molecule that eosinophils need, specifically VACM. They drive chemokine expression, the chemokines that will, again, cause those [INAUDIBLE] to chemotax in the allergic airway. But perhaps the most interesting thing they're doing is on respiratory epithelium. IL13 in particular is turning epithelial cells, those healthy cells in the top right with the cilia that will push out bacteria and clear the airway, and it turns those epithelial cells into goblet cells, the mucus-producing cells that cause our patients to choke and asphyxiate on their secretions. And on the smooth muscle, they're causing smooth muscle hypertrophy. So when you think a bronchial hyperactivity and bronchial spasm, those are largely IL4 and IL13 effects. And the neat thing is, you can block both of these cytokines with one drug. And you can do it because, in addition to sharing a lot of biologic activities, they share a receptor as shown here. So the type 1 receptor, shown on the your far left, is this IL4 receptor with the common cytokine gamma chain that lots of cytokines use. IL4 exclusively uses that receptor. But there's also a type 2 receptor, what gives that IL4 receptor chain now with the IL13 receptor chain, that both IL4 and IL13 use. More complicated than what you need to remember. The takeaway point here is that this drug, dupilumab-- du, as in 2-- by binding the IL4 receptor alpha chain locks both IL4 and IL13. So this is the newest drug we have in our market. And in the definitive studies, as shown here, you actually do see, with three doses of dupilumab in the top three or four bars versus the placebo, there actually is a modest improvement in lung function. But again, what drove the FDA to approve this drug is reduction in exacerbation rate, anywhere from 54 to 33%. So the main outcome, exacerbation. So what I've presented up until now is conditional human IgE, IL5, Il4, 13 knockouts. What the takeaway message, over and over and over again, that these drugs, or going to Davos in Switzerland, prevents exacerbation, but doesn't really do anything to day-to-day asthma. And this really caused me to completely rethink what the disease asthma is. We have a couple people who survived my medical school lecture here. But one of the jokes I always give in my medical school lecture is, is there an asthmatic in the audience, and what they like to volunteer for study? But I can try it here. Is there an asthmatic here would like to volunteer for one of my studies? That is the right-- oh, bad answer. [LAUGHTER] Because, I always follow that with, our volunteer has just agreed, at the end of the lecture, to donate his lungs to one of our nonasthmatic volunteers and his bone marrow to another nonasthmatic volunteer. If you have an asthmatic, nonasthmatic gets the bone marrow, m asthmatic gets the lung. Who gets the asthma? Now, for the first 30 years of my life, from the Harding administration through the Reagan admin-- no-- I would have sworn that this was a disease of the bone marrow. It's everything we were taught. It's B-cells making IgE, type 2 cells making IL4, 5, and 13. But we did all those experiments. So we made the conditional knockout human. So we got rid of the IgE, we got rid of all those T-cell cytokines, everybody still had asthma. So that's a problem. So how do these Th2 cells get made? Because I am now absolutely convinced this is a lung disease. You don't get asthma until your lungs decide you really need to have asthma. So the current model is that in genetically or otherwise predisposed individuals, there develops a key central role for these three epithelial cell cytokines. Don't memorize them-- the names aren't important. But the concept is, you have an airway that is being damaged, that is sensing danger. It could be a microbe, mycoplasm, rhinovirus, RSV. It could be an allergen in the top there. It could be a lightning bolt hitting your airway. Either way, the lungs are getting damaged, and they misconstrue the damage as being caused by a helminth. And they are making this evolutionarily-preserved, stereotypic response to what they think is a helminth, and they're making these three cytokines-- IL25, IL33, TSLP. And these three cytokines act on both the dendritic cell that's processing and presenting antigen, and the naive T-cell that is seeing the antigen. And the signal they are sending is, when you drive that naive T-cell to become a mature T-cell, be a Tg2 T-cell and make the IL4, and IL5, and 13. Now, what's really interesting about this phenomenon is those cytokines are indeed acting on naive T-cells, but they also act on an awful lot of other innate cells. My favorite cell, the mast cell. Mast cells, we know, are packagers of histamine. But they're also patterns of cytokines. And it's the Th2 cytokines-- it's IL4, IL5, and 13. One of the hot, new cells in the world of asthma is these innate lymphoid type 2 cells. These are cells that look like lymphocytes. They don't have a T-cell receptor. All they do is recognize danger signals-- these three cytokines-- and respond with production of, again, IL5 and IL 13. So in point of fact, once you have epithelial cells making those three cytokines, you don't need the naive T-cells or the Th2 cells. You now have this state where there's permanent production of the cytokines you need to perpetuate a change Th2 process. And of course, the epithelial cells are making those three cytokines. They're also making chemokines, cytokines, like the eotaxins, like RANTES that are activating and recruiting eosinophils. So the current model I have, which fits the data, which is that once your lungs decide to get asthma, that's a life sentence. It never goes away. And it doesn't go away when you give any of these knockout drugs. It doesn't go away when you go up to Davos for four months. You've created a new type of epithelial cell, what I call respiratory epithelium asthmaticus, that is now permanently differentiated to produce these three cytokines, and the eotaxins, or whatever. And those cells are going to make it. When they divide, the daughter cells are going to make these cytokines. And the disease will stay with you for the rest of your life. So respiratory epithelium asthmaticus, this is a lifelong sentence, and that is what's driving day-to-day asthma and the perpetuation of the disease. So in summary, for this last part of the talk, evidence for a compelling, dominant role for the adaptive immune system in established asthma is surprisingly poor. We've knocked out all of those adaptive immune cells. It doesn't fix the disease. Allergens, acting through the adaptive immune system, cause exacerbations. They don't drive what's going on day-to-day. And here's the best argument I have for why it's not a disease of the adaptive immune system. I had only one person who wanted to volunteer having asthma. How many people here have hay fever? So everybody in this room with hay fever has a fully-armed, adaptive immune system. You have B-cells that are pouring out IgE to every allergy you're allergic to. Every mast cell of your body is covered with those IgE antibodies that are specific to cats, grass, mite, whatever. You wouldn't have that IgE if you didn't have T-cells, the Th2 cells making IL-4, 5, 13. If this were an adaptive immune disease, everybody with hay fever would have asthma. And that's just clearly not the case, only about 10% do. You only get the asthma when your lungs decide you need to have asthma, or more precisely, something happens to the epithelial cells to drive that epigenetic differentiation. So this is the current model that I work with, which is that asthma, day-to-day symptoms, that's your epigenetically-programmed epithelial cells producing the eotaxins, RANTES, the three cytokines I talked about, IL25, 33, TLSP, driving mast cell activation, activation. Basically, the bronchospasm, decreased lung function, sputum production, cough, daily symptoms, all the things that drive day-to-day asthma. Now, you get your rhinovirus infection, or who here owns the cat and want to invite me over for dinner? That wasn't very nice. [LAUGHTER] I go visit my new friend with the cat and get the asthma exacerbation. That is where the adaptive immune system kicks in, with B-cells causing a surge of IgE production, Th2 causing Th2 cytokine storm with IL4, 5, and 13. And that's where when we use the targeted therapies, anti-IL4 receptor, anti-IL5, anti-IgE, we can prevent exacerbation. So where are we going in the future? I'm convinced that while at present we really do a great job with exacerbations, if we really want to perhaps attenuate the day-to-day symptoms, maybe we have to go upstream further and target the innate immune system, specifically the lung cytokines. And these are the drugs that really excite me for where we're going in the near future. So last slide, takeaway messages-- asthma is a wastebasket term. It is numerous, distinct diseases. Each disease has its unique pathogenic mechanism, and each disease demands its unique therapy-- personalized medicine. Our specialty is no different from everyone else's in this room. Unimodal or guideline-based therapy, such as those produced by the NIH, result in many asthmatics being provided agonists, like inhaled steroids, that may provide little or no benefit. Asthma treatment has to be individualized. And my last thought for the future is that I think these anti-epithelial cytokine therapies are the future and where we need to go. And with that, I will conclude and invite questions. Thank you. [APPLAUSE] Thank you. It was a great lecture. The discussion reminds me of the old Th1 and Th2 switching with [INAUDIBLE]. And I wonder, so asthma is common enough and the phenotype is common enough, that it must offer some evolutionary advantage. So I wonder if those with asthma who are predisposed towards a Th2-type of response, are they protected against helminths in the lung or other h responsive diseases where it might be helpful? I would love to say yes, but can't, for the simple reason that there is no evidence that any person who needs to make a Th2 response in response to a helminth can't. I mean, the real change in the last century, is not that people who are getting infected with these helminths aren't making Th responses to them. The real mistake in what we've done to human beings in the last century is all those people who put their hands up in this room, all these people who are suddenly conflating cat, alpha gal, ragweed, penicillin, whatever, as a helminth. It's not that we've-- you understand? The ability to respond to Th2 was always there. So it's not adaptive under certain circumstances? It's epigenetic and maladaptive? The only [INAUDIBLE] I can find having Th2 disease, that it is associated with incredibly high intelligence and good looks. No doubt. Thank you. [LAUGHTER] Doctor, what do you think the role of environmental toxin, [INAUDIBLE] types [INAUDIBLE] ability of change [INAUDIBLE]? Yeah. So the question is, what is driving the original danger signal. And there's a lot of great evidence. In children, it seems to almost certainly be viral infections that are the precipitating insult. But there's a lot of data supporting the concept of ozone nitric oxide, diesel exhaust particulates, other things. The lungs sense the danger, and in whatever it is we've done through the hygiene hypothesis, whatever that is, they think that the danger is a helminth. So some of the best evidence to support that is, you can-- where's my cat owner? So the average cat can deposit one pound of fel d 1 a year. I think that's what you told me when I was a fellow and you came to Tufts back in the Harding administration. I may be old, but he trained during the-- [INAUDIBLE] Yeah. I mean, the cat doses are massive. So the point I just wanted to make is, I got into this field because of the stunning question which people always ask is, what's wrong with you [INAUDIBLE]? What's wrong with your immune system that you're responding to a cat? And I said, no, you've got the question backwards. How can you inhale that much foreign protein into your lung a day and not have asthma? But the data support the concept. You can inhale the cat and be fine. Maybe you can be exposed to ozone or get a rhinovirus and be fine. What you don't want to do is do that kind of environmental insult and be exposed to the allergen, because it's that combination that seems to synergize. One activates the innate immune systems and neuritic cells. The other is having the wrong allergen. And the combination seems to be what really makes this process go forward. Yes, sir? I wanted to ask you about twitching airways. [INAUDIBLE] talking about [INAUDIBLE] that airways prove mostly basically as an empirical length dimension. [INAUDIBLE] at least can sense this [INAUDIBLE] level. And one of the treatments that people used for asthma [INTERPOSING VOICES] Sighing. [INAUDIBLE] and giving themselves the [INAUDIBLE]. Is there any difference? Yep. And first, comments on that. And second is-- Yeah. [INAUDIBLE] two different types of [INAUDIBLE] So this is some of the best work Tom did back in the last century, where he blamed all of asthma on television. And the reason he was right was you can do-- so the twitchy airways and what you're talking about in these tension receptors, we measure the twitchiness with methacholine. You non-asthmatics you can inhale as methacholine as I can give you, nothing will happen. An asthmatic response to methacholine was bronchospasm one of ways we diagnose the disease. Now, when you do a breathing test for that, it involves taking in the biggest breath you can and then forced maneuver, which is stretching the fibers. The real difference in a normal and an asthmatic is the response to that stretch response. Every single person in this room, if I measured your lung function using conductance, i.e., you don't get to take a deep breath in, we're just going to measure airway resistance. Every single person in this room will react to methacholine if I don't let you take in that sigh, that deep breath response. So all these kids who are sitting indoors, watching TV, and not breathing more than tidal volume, that was one of [INAUDIBLE] theories about asthma that actually is correct, like most of them. Second question, I think a lot of that hypertrophy is really an IL13-driven phenomenon. I don't know how well it's been studied in the IL17 disease. That's a good question. I don't know. Yes, sir. And i response. What? Nutrition. Nutrition. And the answer is, yes. Although, the study-- is there someone who-- So the question is, Th1, Th2 and nutrition. I know there's some neat studies with things like glutamine in the diet. Do you know more about that, Tom? Yeah. Specifically, [INAUDIBLE] for example. [INAUDIBLE] Yes. And the changes in the [INAUDIBLE] Right. [INAUDIBLE]. So there is a lot of interest in the [INAUDIBLE] Yeah. And [INAUDIBLE]. Also, some of these allergens, [INAUDIBLE], they are also [INAUDIBLE]. They're also like-- Like, I'm [INAUDIBLE]. And so they can really affect the [INAUDIBLE]. Really a learning group [INAUDIBLE] themselves. And they're all [INAUDIBLE] themselves. They are also really [INAUDIBLE] people who have to improve diet. [INAUDIBLE] So ask the last question here, and then [INAUDIBLE]. [LAUGHTER] Thank you. Yeah. [INAUDIBLE]-- well, go ahead. My question is, has somebody looked into nutrition and like iron deficiency, anemia, or other nutritional factors and how does it affect the risk of asthma in populations. So the long answer is a one-hour lecture on the hygiene hypothesis. Because I did hint at this as something we've done to herself. Asthma doesn't exist in the paleolithic diet. And diet is something that people are hugely interested in, although most of those d and I think you're right, because there is a lot of data supporting exactly what you're saying, is nutrition and Th1, Th2 immune deviation. Although a lot of the focus now is what that diet is doing to gut biome and how that's driving it, and how we've destroyed the infant's gut biome with antibiotics and everything else. I think we have time for one more question. Joel? [INAUDIBLE] from the practical standpoint of [INAUDIBLE] asthmatics [INAUDIBLE] everybody, or [INAUDIBLE] What should we do most effectively to help people identify if they may or may not [INAUDIBLE]. Of course. OK. The short answer actually is, in the real world, you live by the NAEPP guidelines. And you should, because they work for 70% of patients. But the patients are going to let you know that they're the ones who the guidelines aren't working. So a short answer is, if you put them on the inhaled steroids, you can add the [INAUDIBLE], everyone's doing great, you're done. If they're not doing great, then the question is, is it steroid resistance or is it one of these neutrophilic diseases. One of the hints of the steroid resistance is, what are the eosinophil counts? Because if they're still screaming high, that's the person who we're going to start thinking about one of these IL5 modalities. If in doubt, you're not going to do it. But I'll tell you right now, there's a reason why I'm going to join clinic with Drew Harris, and why Drew Harris and Charles Malpas are my two closest friends. Because we're doing a lot of bronchoshopies. And not only are you finding the neutrophilic disease, it's amazing how much chronic and-- I shouldn't say infection, because I see Jerry in the audience-- colonization with bad things that shouldn't be there that aren't making the airway disease any better. I think we should probably finish there, because it's 1:15. But I'm happy to stay around afterwards if people have questions. Thank you. [APPLAUSE]