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Insights in Pediatric Food Allergies

– Welcome everyone to Wednesday Nite @ the Lab. I’m Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for the Division of Extension, and on behalf of those folks and our other co-organizers, Wisconsin Public Television, Wisconsin Science Alliance, and the Wisconsin Alumni Association, thank you very much for coming to Wednesday Nite @ the Lab. We do this every Wednesday night, 50 times a year. Tonight, it’s my pleasure to introduce to you Anne Marie Singh. She’s a professor in the Department of Pediatrics here. She was born in Buffalo, New York, and went to high school in Williamsville, New York, which is a suburb of Buffalo. Then she went to the University of Rochester and got her undergraduate degree in chemistry. She went to the Albert Einstein College of Medicine in New York City to get her MD degree, she did a residency in Philadelphia, and then she came to UW-Madison to do a fellowship.

And that was the one in allergy?

– Anne Marie: Yes.

– Great. Then she was on the faculty at Northwestern University’s medical school in Chicago for nine years. And then in 2017, she returned here to UW-Madison, and is again in the Department of Pediatrics. Tonight, she’s gonna talk with us about something, if I might add, we’re all itching to hear about. [audience laughing] Yes, she’s here to talk with us about insights in pediatric food allergies. As somebody who had tiny little food allergies, but a lot of shots when I was growing up, it’s gonna be very interesting to hear how things have changed in the last 50 years. So please join me in welcoming Anne Marie Singh to Wednesday Nite @ the Lab. [audience applauding]

– Okay, great. Thank you everyone for coming tonight and thank you for that very kind introduction.

So tonight I’m gonna be talking about food allergy and insights in pediatric food allergy. And so the first half of my talk, I want to talk about the disease, basically the clinical disease, what is a food allergy, what’s not a food allergy, how we diagnose food allergy, what’s coming down the pike with treatments, and kind of where we are with the clinical care of food allergy. So that’ll be the first half of the talk. The second half of the talk I want to talk, it’ll be a little bit more research-focused, and kind of the burning question I’m imagining on many people in the audience today, and also among many allergists, is it seems like there’s a lot more food allergy than there used to be. And the question is, is that true? Is there really more food allergy than there used to be? And if so, why? And then, what can we do about it? So then, I want to talk about the future of food allergy. Can we prevent food allergy? And what are some of the treatments that are going on for food allergy? And near and dear to my heart is what is UW doing about this, right? So how can we contribute to the food allergy field? Okay, so what is food allergy? So this is the medical definition that I have on the top of the slide here. And this is kind of based on the clinical practice guidelines, and food allergy is defined as an adverse health effect that arises from a specific immune response, and occurs reproducibly on exposure to a given food. So that’s a lot of information packed into one sentence. But I tried to highlight the key things. So the first thing is, it’s an immune response.

So this is an immune-mediated phenomenon, or something that’s happening and your immune system is getting turned on when reacting to a food. It has to occur reproducibly, which means it needs to happen every single time you eat the food. And not sometimes and not others in most cases. And it’s on a given food. So, when we think about an adverse food reaction, there are many reasons why a person might eat something and it can make them not feel well, right. There are many many reasons, some of which are food allergy. And so when we think about this is, and I know he mentioned this, but I’m a pediatric allergist immunologist, so let me just back up and say that. So that’s the lens from which I’m speaking today. So when we think about someone who says, “Oh, I ate a peanut and I didn’t feel well,” the first question we try to answer is, does this sound like this is an immune reaction? Was it immune-mediated or was it nonimmune-mediated? And so when we think about an immunologic reaction, there can be different types of an immunologic reaction. And almost everything that I’m gonna talk about today is the left part of the slide, which is an IgE mediated reaction.

So our immune systems make different types of antibodies and we all know, antibodies help us fight infection and things. And that’s usually IgG, and IgE are the antibodies that were originally made to help us fight parasites. Well, in the U. S. hopefully, many of us are free of parasitic infections, and IgE now is really considered the allergic antibody. And so, but IgE mediated food allergies are often hives or urticaria or anaphylaxis, but there are also non-IgE mediated food allergies that I’m not gonna talk about today. And the one that is probably most familiar to everybody in this group would be like celiac disease. So this is an immune-mediated reaction to wheat, but it’s not IgE mediated. And so that’s kind of why it’s in the non-IgE mediated group. When we think about other types of adverse food reactions, these are kind of a lot of the things that fit into the non-immunologic.

So something that’s really easy to understand. If you eat rotten eggs and you get vomiting and diarrhea, obviously that’s not a food allergy. That was food poisoning. You got sick from eating rotten eggs. So just because you eat something and it doesn’t make you feel good, doesn’t make it a food allergy. And so there are known things like food poisoning or scromboid fish poisoning. There are pharmacologic reactions. If you drink a lot of coffee and get jittery, that’s not very surprising. That’s from the caffeine in the coffee. There are enzyme deficiencies, so lactose intolerance or lactose deficiency.

And then there are other disorders, like if you can’t digest your food properly because you’re missing some pancreatic enzymes, or if you have liver disease or things like that, you can have reactions to foods, but that would not be considered a food allergy, at least the type of food allergy I’m gonna be talking about today. So as an allergist, we talk a lot about what is a food allergy versus an intolerance. And so when I ask a patient, “Tell me what happens when you eat that food,” or “Tell me what happened when you ate that. ” These are some of the clues that I’m listening for to try to help distinguish if someone’s having an allergic reaction or an intolerance. So if you remember from that definition, I said it happens reproducibly and reliably every single time you eat the food. And so that means, even if you only eat a small amount of the food, so a trace amount of the food should trigger reaction if it’s an allergy. If it’s a more of a dose-dependent reaction, meaning I eat a little bit and I’m fine, but if I eat a lot, that’s when I get sick, that’s more likely to put you in the intolerance. We talked about the immune-mediated and nonimmune-mediated, and not always reproducible and reproducible. I put a little asterisk in here because for the reproducible and immediate, because when we talk about updates in the last 50 years, this is one of the biggest updates that we’ve found, and I’m not gonna talk too much more about it later in the talk, but that’s especially in children, there are children who are allergic to milk or egg who can’t drink a glass of milk or can’t have cheese or ice cream, but they can eat milk if it’s cooked, what we call extensively heated milk, or baked in a cookie or a muffin or something like that. And the same is true for egg, and now very new, there was just recently an article in The New York Times about it.

There’s a delayed allergy to red meat, and that has to do with the saliva from a tick bite. So, and it’s the lone star tick and it’s usually in Appalachia, and surprisingly it’s also in Wisconsin, but it’s more common in Appalachia, and these patients will get a delayed reaction to red meat. So normally it’s a trace amount, reproducible and immediate, but there are a couple of exceptions out there that I just highlighted. Okay, so now we’ve talked about what a food allergy is. So it’s an immune-mediated response, that’s that IgE mediated or that allergic antibody mediated. And so the symptoms can range from atopic dermatitis or allergic skin disease, all the way to a life-threatening reaction called anaphylaxis. And I’m gonna talk about that in a little bit more detail on a couple of slides. We just talked about how this is different than a food intolerance or food sensitization. And for the research part of the talk, I’m just gonna, early in life food allergies, often co-expressed or at the same time, children will often have that allergic skin disease or atopic dermatitis and food allergy. So I’m just laying the groundwork now, ’cause we’re gonna revisit that in the second half of the talk.

There are eight foods that will trigger over 90% of this IgE mediated food allergy, and they’re listed on the slide. So milk, egg, wheat, soy, peanuts, tree nuts, fish, and shellfish. And that’s just a little graphic of all the top allergens. What’s really interesting about the food allergy world now, is there are now what we’re calling emerging allergens, or there are now foods that maybe 10 years ago didn’t cause food allergy, but it’s causing food allergy today. And this is a puzzle, and we don’t really understand why. And sesame and some of the seeds is one of the most common emerging ones. Legumes including lentils, chickpeas, beans, peas, green bean, that’s another one of the emerging food allergens, and particularly in adults, less so than in children, there’s this emerging fruit allergy including to kiwi and avocado, and then there’s been some case reports in Europe at least of apple allergy, hasn’t made it to the U. S. really yet, but in Europe. So not only we’re gonna talk about food allergy is increasing, but now we’re developing allergies to more foods.

And this is a puzzle for the food allergy community. So this is a lot of information, and I just kind of put it up here to highlight that depending on your age, there are usually different triggers. So young children are most often allergic to the egg, milk, and then soy and wheat, and then peanuts, tree nuts, and seeds. But if you think about adult food allergy, that’s more likely to be nuts and fish. So peanuts, tree nuts, fish, and shellfish. And what’s really interesting, and this is an area of research in my lab, is most children will actually outgrow their food allergy, especially if it’s to milk, egg, wheat, or soy. So if you have a fish or a nut allergy, you’re less likely to outgrow that and more likely for that to be lifelong. But if you’re allergic to one of the other foods, milk, egg, wheat, or soy, that’s almost universally outgrown. The sad part is, just like with everything with food allergy, is this natural tolerance or this ability to outgrow food allergy is occurring later in life. So when I was a fellow here, as you heard in the introduction, that was in 2005, I was taught by my teachers all children will outgrow their food allergy by the time they start kindergarten.

It’s just a disease that everybody outgrows. Obviously, now everyone in this room knows this is not true anymore, and food allergies are persisting into adulthood, and that people aren’t outgrowing them as quickly as they used to. And this is a question in the food allergy field. So what are the symptoms of a food allergy? And I kind of listed them here, and they can basically affect any organ system. Symptoms usually occur within minutes, and they typically occur within two hours. So normally, it will happen within 15 to 30 minutes of eating a food, but can happen up to two hours. And when we talk about what symptoms, it can affect any organ system, and I kind of have them up on the slide, you know, itching, flushing, hives, swelling, rash, itching or tearing of the eyes, coughing, wheezing, sneezing, difficulty breathing, the dreaded throat closing of an anaphylactic reaction. It can affect the GI system, nausea, vomiting, belly pain [coughing] excuse me. The cardiovascular system, heart racing, heart slowing, changes in blood pressure and dizziness. And then in the neurologic system, food allergy patients will often describe what’s described in the medical textbooks as this impending sense of doom, which for whatever reason, they eat a food and they’re like, they don’t feel well and they think something really bad is gonna happen, and they can get panicked.

And this has got to do with a neurological change that happens when they eat the food allergy. So here are some pictures of some of the patients that I’ve taken care of. So here in the upper left, if I can get my mouse here, is a little girl who was eating actually beans and legumes, and this is a picture that her mom gave me, and you can see she’s got some eye swelling, and some lip swelling, but she’s happy. She’s fine, right. We’ll treat her, she’s gonna get better. Here’s another patient, and here you can see this diffuse itchy rash, or the urticaria or hives. This is a patient from a food challenge and we can see again, lip swelling and hives. It’s hard to appreciate it in the picture, but there’s some redness of the eyes, and some tearing. Here’s again some lip swelling, and then this patient on the left, I’m a little bit more concerned about, because they have rash and lip swelling, but obviously they’re not really, they’re really sleepy, their mental status, their mental ability, they’re difficult to arouse. And obviously, I was concerned enough.

It’s hard to see, I can’t get there. Oh there it is, in the corner here, this is a blood pressure cuff because she started to drop her blood pressure, and the patient did well, but she required multiple doses of epinephrin, she got better and she’s fine. But these are all kind of the different things that can happen in food allergy. So what happened with that last patient that’s different than the other patients in the picture? And that last patient had anaphylaxis. So when people talk about and anaphylactic reaction, or what is anaphylaxis? The medical definition is two or more organ systems that get affected, or a single organ system that’s life-threatening. And there are certain foods that are more associated with anaphylaxis than others. And peanuts, tree nuts, and seafood are more common throughout all of food allergy patients, and in the really young children, it’s more likely to be milk and egg. And so that patient that I showed in the picture, that was to egg in that little girl. Unfortunately, anaphylaxis remains potentially fatal, and there are about 150 deaths per year in the United States. And there are some risk factors associated with who is more likely to die of an anaphylactic reaction.

And that’s a patient who has asthma, a patient who doesn’t get the proper treatment, so they don’t get their epinephrin. Obviously, if they’ve had a previous severe reaction, you’re at risk for another severe reaction. And then adolescents and young adults. And the thought is in that age group, it’s the typical age group when they don’t want anything to be wrong with them, they don’t want to be different than their friends or peers, so they don’t tell anybody they don’t feel well, they don’t give themselves their epinephrin, and then that’s kind of what can lead to a fatal reaction. And then if you don’t have skin involvement, then sometimes people get confused, like, “Oh, but I don’t have hives, I’m not itching. “This can’t be a food allergy. ” And then that can be a risk factor. Okay, so how do we diagnose food allergy? So, the gold standard is an oral food challenge, and that’s where the patient comes into my clinic, and they eat escalating amounts of a trigger food over several hours. So I did two of these on Tuesday, in my clinic on Tuesday, where I’m trying to see if someone truly is food allergic, or more likely when I do this clinically, it’s because I think someone has outgrown their food allergy and I want to prove to the family and to myself that it’s safe for them to eat, and they’ll come in. And so for a peanut challenge, they’ll bring in peanut butter or they’ll bring in PB2.

Have you guys seen that now? That like dehydrated peanut powder, and they literally start with milligrams, and they eat milligrams, like a tiny tiny amount of the food, and they wait 15 minutes and I watch them, and if that goes okay, then they eat a little bit more, and then they wait 15 more minutes, and they eat a little bit more, until after about between four and seven steps, they’ve consumed a whole serving, and then they stay with me for at least two hours, and I make sure they don’t have a delayed reaction. So that’s what an oral food challenge is. So obviously, this is risky, right? I’m feeding someone they can be potentially allergic to. It causes significant anxiety in parents and children, and it’s time-consuming, labor-intensive, and expensive. So we often try to make the diagnosis in other ways. And so we’ll do that based on the clinical history and confirmatory testing. So there’s two types of confirmatory testing, and there’s skin testing and IgE testing. And I’m sorry, the pictures don’t show very well, but I just kind of, for anyone who has not had allergy testing, I wanted to put these pictures in, just so you could see what it’s like. So basically we usually do it on the kind of front of your forearm, and we put like little drops of purified antigen or purified protein from the food on your arm. And then we do a little prick.

So what the caretaker is holding there is this little tiny, I always tell the little kids, it’s like a fork, but you know it’s like a little metal fork. It’s not quite a needle. And then we do a little scratch under the first layer of skin, and then we look to see in the lower picture here if the skin reacts. And so if we get a big red hive, that’s considered a positive test. If nothing happens here, that would be a negative test. And so then we use the skin testing in combination with the clinical history, using those clinical clues that I showed earlier in the talk to decide whether or not I think somebody has a food allergy or not. And if I’m not sure, or the parent’s not convinced, or no one’s convinced, then we go to the food challenge. So that’s how we diagnose food allergy. What about the treatment of food allergy? So unfortunately, there are no approved treatments for food allergy. So most of the treatments, or what happens when I diagnose someone with food allergy is education, education, education.

So teaching a patient and their family how do they live with this diagnosis. And the issues that you have when you’re a toddler, or you’re going to daycare or preschool, are different than the issues than if you transition to school, which are different than the issues when you’re a teenager and you’re start leaving, you’re not under the control of your parents, which are different than when we say goodbye and we kiss our kids and send them to college. And then they’re responsible for all their own foods. So a lot of what I do is teaching families how to live with the food allergy. And the main thing I have to say is strict avoidance. So you can’t eat this food. You have to read every label, you have to be cautious of cross-contamination, you have to be cautious of hidden ingredients. I do a lot of nutritional counseling. I work really closely with the pediatric nutritionist in my clinic, and we ensure that feeding and nutritional needs are being met, and then they get this emergency plan, because unfortunately, if you look at the research, 20% of patients will have an accidental ingestion per year. So I need to prepare my patients for when you– not if, when you accidentally get in touch with the food that you’re supposed to avoid, what should you do? And so this is a picture of, every patient that I see leaves with an action plan and it basically says, if you have these symptoms, do this.

If you have these are the more severe symptoms, it says inject epinephrin immediately, call 911, blah, blah, blah. And then the patients need to carry an epinephrine autoinjector. So here are pictures of the two major epinephrin autoinjectors. And basically I teach them how to use these devices. So they need to carry these devices and take them with them everywhere they go. So if you don’t have a food allergy but you host a grandchild or a child or someone at your house, you may see these when they come. And I teach them how to use it, and then we follow them to keep going, how you live with the disease. And then as I said, I always try to be hopeful, like, you will likely outgrow this disease, but we have to follow you closely, and see when that will happen. So what does avoidance really mean? I mentioned this already. You have to read every label, even foods that you may have eaten before, in case the food manufacturer changes how they do it.

I counsel patients on special circumstances. How do you go out to eat with a food allergy? I talk to them about, we practice in the office. What are you gonna say to the waiter? What are you gonna tell your friend at the table in kindergarten? Like these are the things we kind of go through. We talk about birthday parties, play dates. The official recommendation is that you’re supposed to avoid foods with advisory labeling, so may contain or processed in a facility with peanuts. So here’s an example of what if someone comes in and they have a milk allergy. And so this on this slide, these are all the different ways milk might be listed on an ingredient list. So I took this out of the slide ’cause I didn’t want to bog it down. But when a patient sees me, they get a food-specific handout that says, Oh, you’re allergic to peanut, I print out the peanut handout, you’re allergic to milk, I print out the milk handout. and it kind of walks patients through, these are some of the hidden words that equal milk or milk protein that could be an allergy too.

So, so here’s an example of all the different ways that milk could be listed. So that is kind of the first half of the talk where I wanted to talk about clinically, what is food allergy, how we diagnose it, and what I spend a lot of time in my office talking to patients about. So now I’m gonna move on to the second half of the talk, which is a little bit more of the research, and that’s state of the art, and what’s going on with food allergy. So how common is food allergy, right? So they talk about a food allergy epidemic. So 32 million Americans are thought to have food allergy, which means 1 in 13 children and 1 in 10 adults. So I can tell you when I went to school, I can think of maybe one person, in all of my childhood, that had a food allergy. It just wasn’t something that I lived with or knew much about. And these statistics bear out. I have two children, they’re both school-aged, and there’s always a food allergic children in every class, every single birthday party, there’s somebody with a food, food allergy now, and it’s just a part of their life. So like for my kids, I remember when my daughter wanted the birthday party, she came home one day, she’s like, “I want to invite “Henry to my party, but Mom, “he can’t eat peanuts and wheat.

” And she knows, and they all know, and I’m like, “Okay, we’ll make that happen. ” I figure if I can’t make that happen for that child, nobody can, right? [audience laughing] So I can make this happen for that child. So food allergy is more common. 377% is the increase in like, insurance diagnosis codes for medical claims of anaphylactic food reactions between 2007 and 2016, so it really is increasing. This is just some of the nuance. Self-reported food allergy is about 10 to 18%. Physician-diagnosed food allergy is somewhere between 3 and 8%. And so we think the prevalence is about 8% of Americans have a food allergy. So what is this epidemic? So the incidence of food allergy continues to increase, despite our best public health efforts. And I kind of walked through some of this.

We don’t need to belabor this. So why is food allergy increasing? And so, these are kind of some of the thoughts in the food allergy community about why there is so much more food allergy. And one of the reasons is increased awareness. Everyone now knows about food allergies. Everyone’s on the radar for it, and we pay attention to it. And so maybe because there’s so much more awareness, there’s increased recognition. And I think that’s probably true, because we’re recognizing milder disease and more of the younger kids that outgrow it more quickly. So I definitely believe that to be true. We know from some of these birth cohort studies and these population-based studies, that more patients who get sensitized become allergic. So I didn’t talk about this earlier, but you can sometimes have IgE antibody to a food before you develop the food allergy, and more people are crashing through that checkpoint and going from sensitized to becoming allergic.

And so one of the example, there’s this very big health nut study, it was a population-based study where they looked at young children who are comprehensively evaluated, and 10. 4% at age 1 were allergic to egg, peanut, or sesame. There’s another part to this story, and that’s if we recognize more food allergy, we’re taking that food out of the person’s diet, and now we know, which I’m gonna show some of the research in a few slides, that oral exposure, if you can handle it and it doesn’t cause a reaction, can be protective or almost a form of therapy. So maybe by recognizing more food allergy, we’re being more cautious, and then we could also be making the problem worse in that way. And then obviously, if I grew up and there are no food allergy in my children, it’s a part of their lives, food allergy, that genetics doesn’t, human genetics don’t change that quickly in one generation. Then there has to be some changes in our environment. Something about our environment and our environmental exposures is leading to this increase in food allergy. So why are more children developing food allergies is the cocktail party question, the clinical question. And so if I turn that into a research question, what are the environmental exposures that alter food allergy risk? And so I’m going to bring up the hygiene hypothesis. So the hygiene hypothesis is this hypothesis that was actually proposed in the late 80s, 1989, by a British epidemiologist named William Strachan, and basically it was based on these observations that he saw that children who had more viral infections, or children who had older siblings, or children who grew up on a farm, these dirty environments, were less likely to develop asthma.

And so that became the hygiene hypothesis, that maybe we’re too clean, and because we’re too clean, our immune system wasn’t fighting what it was designed to fight. And so now it starts fighting things that it’s not supposed to fight. So we’re not eating dirt anymore. [audience laughing] And so then we can get dirty. And so here are some of the factors. So you know, less exposure to animals, pets and livestock, older siblings was a risk factor. And then these viral infections early in life. And so this is kind of showing this in kind of a mechanistic way, and the important thing to take from the hygiene hypothesis is emphasizing that the immune system changes. So you’re not born with an immune system that you keep forever, that your immune system is prone to these influences in the environment, and that different exposures can infect your immune system in different ways. All right.

So what’s important about the hygiene hypothesis is that all the factors have really been investigated for asthma and nobody had ever looked, are the same things that are a risk factor for asthma an important risk factor for food allergy? So the question I wanted to ask, do hygiene hypothesis factors affect oral tolerance in the food allergy balance? And so to answer this question, I collaborated with an epidemiologist in Chicago, Lurie Children’s, and we did this Children’s Memorial food allergy study, where we enrolled over a thousand families, and we tried to look at what are the factors that are associated with food allergy. So there are a thousand families and so, both parents and siblings were enrolled. And you can see on the slide, 527 don’t have food allergy. 832 of the children do have food allergy. 953 don’t have asthma, and 406 have asthma. So these are the same children. We just divided them into whether they had food allergy or asthma, because as I mentioned, everything about the hygiene hypothesis previously had been about asthma. So we looked at these hygiene hypothesis factors, age, gender, ethnicity, income structure, maternal food allergy. And then you know did they go to daycare? Were they delivered vaginally or by C-section, were they breastfed? Did they have pet exposures, do they have infections? And basically, when we looked at all of these things, and all of these things have been associated with asthma risk, the only one of these factors that were associated with food allergy risk was maternal food allergy, or if the child had other allergic disease. So this is kind of our first clue that maybe the hygiene hypothesis is different in food allergy than it is for asthma.

So then we wanted to hone in on this early life infection, because early life infection has been the strongest predictor of asthma risk in the hygiene hypothesis. So this graph, on the bottom, you can see these are all the hygiene hypothesis factors that have previously been published to be associated with asthma, and our study recapitulates those findings. So children without asthma are in blue, children with asthma are in red. And you can see if you got antibiotics early in life, if you had more common colds early in life, more severe lower respiratory infections. RSV stands for respiratory syncytial virus infections. If he had ear infections, pneumonias or skin infections, just like you would expect, those children with those infections were more likely to have asthma. When we look at these exact same children, and we look at these exact same factors, you can see that the, all of the statistical significance goes away. So these children, these are not risk factors for food allergy except for skin infection. So that said to me, there’s something different about a skin infection that could be relating to food allergy risk. So that led to the next question.

So why would skin infection be associated with food allergy risk? And so as a pediatric allergist, or as a pediatrician, when we think about skin infection in the first year of life, children who have allergic skin disease, or an atopic dermatitis or eczema, are much more likely to have a skin infection than children who don’t. So I kind of turn this to bring it into something that I can study. How does eczema or atopic dermatitis diagnosis affect food allergy risk? So to answer this question, I started collaborating with some of the researchers here, and we looked at the childhood origins of asthma birth cohort. So this is a high risk. These children are enrolled in a clinical study before birth, so the pregnant mothers enroll their children, and these children were followed prospectively from birth, and now they’re no longer children anymore. They’re turning 18, 19, and 20 right now. And so, and then every year they come in for clinical visits, and we kind of can get some information about the natural history or what happens with their disease. And what we found was that children with eczema are much more likely to develop food allergy. So if you remember from that slide really early in the talk, I talked about how food allergy and eczema are often co-expressed. I’m afraid to touch my mouse, but so that’s at year one, right? If you look at the year one bar, children if you had a food allergy, the yes, the red.

Sorry, if you had eczema, which is the red bar, then you are much more likely to have food allergies. So that year one bar was kind of known, and been published, and we furthered that observation to show that not only do you have risk at year one, but that risk persists at least throughout childhood. So if you have eczema as a baby, your risk of food allergy persists throughout childhood, all the way through age 18. We tried to quantify that risk by doing an odds ratio, and the odds ratio of having a food allergy is close to 10. It’s a log scale at the bottom. So if you have eczema, you have about between a 7 and then 10 times risk. I’m sorry, if you have eczema in the first year of your life, you have about a 7 to 10 times risk of having food allergy. So what are the mechanisms that could be causing food allergy, and why is eczema associated with food allergy, was the next research question. So this is the only immunology slide I’m gonna put in, and I’m not gonna say too much about it, except to say the top is the environmental exposures. You can see bacteria up on the right, and food antigens and stuff in the middle.

And then those things get uptaken by our immune system. And there’s this crucial cell that’s the green cells right in the middle of the figure. And those are your regulatory T cells. So regulatory T cells are the cells that are thought to be really crucial in turning immune systems, turning on the immune system or turning it off. So they’re called regulatory T cells, because they regulate the immune system. They turn it on or they turn it off. And so that led me to hypothesize that these regulatory T cells were crucial in food allergy, and that food allergy may be happening because you don’t have enough regulatory T cells or they don’t work. So we asked the question, are these cells different in children with or without food allergy? And I did this project with a fellow, Ben Prince, who worked with me in my lab and he’s now faculty at Ohio State, and we looked at 55 children. And to make a long story short, what we find is that regulatory T cells are important, but only if you’re little. You have to be less than six years of age, less than six years old, and then the regulatory T cells seem to be important.

So the purple dots on the left show that younger children who do not have food allergy have more regulatory T cells than children with food allergy, which are the red dots. And that’s really important at zero to six years of age. But if you look after six years of age, that difference seems to go away, and maybe even flip flops. So this is, we’re only talking about regulatory T cell number. Do these regulatory T cells work? So without going into a whole lot of detail about the immunology piece, but we look to see what chemicals these regulatory T cells can make, and how that works for their function. And we do find in the, at the younger ages, there’s no difference in how the regulatory T cells function. They seem to work okay in the younger children, but they have fewer of them. And the older children, when I said the numbers seem to flip flop, like maybe they had more if they had food allergy, but the problem is, they don’t work. So even though they have more numbers, the cells that are there don’t do what they’re supposed to do. So they don’t secrete the messengers they’re supposed to secrete.

They don’t suppress the immune system the way they’re supposed to suppress. So now where my research is going now, is trying to understand what is it about those skin infections or eczema that’s affecting the regulatory T cells. And so we’re doing a lot of work about the microbiome and the bacteria on the skin of children who have skin inflammation compared to children who don’t have skin inflammation, and how that affects their immune system, particularly these regulatory T cells. Okay. So, if there’s no treatment, maybe we could prevent food allergy. So can we prevent this from happening, the the kid in school who has to go to school in a space suit? And so I want to spend just a couple minutes, this is a really exciting development in the field of food allergy. So there is a group, Gideon Lack and his group. He had this really talented postdoc who was from Israel, and then he went to the U. K. for his postdoc.

And what he observed was, in Israel, there was no peanut allergy. And then he got to London and he was like, “What is peanut allergy, “and why is everybody allergic to peanut allergy?” And so he did a study to do an assessment of Jewish children in the U. K. versus Jewish children in Israel. And he found that the prevalence of peanut allergy was over 10 times higher in the U. K. than in Israel. And so he had this hypothesis, because he said, Israeli children eat the snack called Bamba. So that’s the picture there. And it’s similar, it’s basically their teething biscuit.

So as babies are learning to teeth, they’re given this Bamba, this teething biscuit, you know in the U. S. we give Cheerios or puffs to all the little kids. In Israel, they don’t do Cheerios. They do Bamba, and Bamba is made from peanut flour. And so he had this hypothesis that there was something about this early introduction of peanuts that might be preventing food allergy. So he had this hypothesis that dietary introduction of peanut before 11 months would prevent food allergy. So they did a randomized open label study, where high-risk infants are enrolled. That’s the bottom. They go through an oral food challenge, and then if they are not allergic to peanut, they’re either randomized to early introduction, so to eat peanut early in life, or peanut avoidance.

So I, the public health advice at this time was peanut avoidance. So we were telling people, don’t feed peanut to your child ’cause it could give them an allergy. And so this was really a provocative hypothesis and idea. And what he found was that the children that were randomized to the peanut consumption, so that’s the consumption group, no matter if they were sensitized or not sensitized. So that’s the skin prick negative, skin prick positive. Or if you take everybody, there was an overall 81% reduction in peanut allergy in the children that were randomized to early peanut introduction. So this was a landmark study. It led the AAP, the American Academy of Pediatrics, in 2015, to rewrite the infant feeding guidelines. And now we say, you should give your child peanut before one year, and if you’re high risk, you should do it before four months of age. So this is completely different than probably when you all had children and completely different from when I had my children.

So this has kind of been turned around. There are some questions about this though, and that’s does this hold for all foods? And so they did a follow-up study, and I took the data out, called the eat study, and it does not hold for all foods. So they tried this exact same study design, and the children were randomized to consume all those milk, egg, fish, wheat, and peanut versus not. So that’s, and they didn’t find a statistically significant difference in food allergy between the groups, and there’s a lot of possibilities for that. And one of them could be it was just too hard. Like you have a newborn, and you want me to try to introduce five different complementary foods twice a week? So they had a lot of trouble with adherence. Like the new parents weren’t able to adhere to that. But also, it looks like early introduction only works for some foods and not others. And so there’s a lot of work now in the field to say what foods does it work for? What foods doesn’t it work for? When should we be doing it? And the newest data’s coming out that’s showing, maybe this will be helpful for egg, but it doesn’t seem to be helpful for milk, soy, wheat, or fish. But there’s more to come.

So just because it’s true for peanut, doesn’t mean it’s true for everything. So I just kind of wanted to mention that. Okay, so this was super exciting in the allergy world. We finally have a way to prevent at least peanut allergy. And now, now what? And so I want to spend the next just like two slides talking about the future. And so the future, now, what are the– I said there are no FDA approved therapies. What are some investigational therapies? And so one you may start hearing about is oral immunotherapy. And in fact there was just a really big article in The New York Times magazine, if anybody saw that about this. And what this is, is we feed the children something they’re allergic to. And we do escalating amounts.

That’s the initiation phase, and then build-up phase. And so we increased the amount, the dose of say peanut, that they eat every single day, and then there’s a maintenance phase. We get them to 300 milligrams of peanut protein, which is the equivalent of a peanut. And they eat that every single day for a period of well, we don’t really know, but the studies have all been between 6 and 24 months. And then if you make it through all of that, then you can have at least a peanut. So that can take away some of the fear. And interestingly, some of the children could go on and eat 10 times that. So not just one peanut, actually 30 times that. They can eat 30 peanuts, but some patients can’t. And so we can’t predict who gets what we call desensitized, versus who does not get desensitized.

The other interesting piece of that is some patients can develop what’s called sustained unresponsiveness. And all that means is, if you take away the daily peanut, some people remain unresponsive and some people don’t. And if you notice I’m saying, some get desensitized, some don’t, some get sustained unresponsiveness, some don’t. And that is true, and unfortunately we have no way of predicting who’s gonna fall into what buckets. So this is an area that people are really looking into. How can we predict who is this therapy gonna work for, how we can predict how well it’s gonna work for each patient. And the reason why this is important is if you look on the right, the dropout rate, it’s really high because I’m giving you basically a poison. I am giving you something that you are allergic to. 100% of patients will have side effects. The question is, can you live with them? And so maybe the side effect is mild enough, you get an hour worth of abdominal pain or belly pain every single day, and that’s worth it to you.

But up to 20 to 30% of patients will anaphylax, or have that severe reaction from the therapy. And so some of the patients say, “You know what? “It was better to avoid. “I feel sick every single day. “I don’t like this therapy, I don’t want it. ” And some, it’s worth it to them. And that’s obviously a personal choice. Everyone can make their own choice. So this has been submitted for FDA approval. It’s compound AR-101, if you see anything in the news about that. So it’s been submitted for approval.

It’s hopeful and it’s exciting, but obviously, this is not going to be the golden ticket, right? There are a lot of questions and unknowns and a lot of side effects associated with it. I went through all of this, so I don’t need to say this. And so then the other therapy that is pending is epicutaneous immunotherapy or EPIT, or the patch. And so this would be peanut patch, and this is where peanut protein is placed on this little sticker. And then you change the amount, you change the patch every single day for 24 hours, and then we see if we can do, instead of having to swallow the food, is the patch application good enough? And what’s nice about the patch is no one’s anaphylaxing ’cause they’re not swallowing anything. They may get some itchiness from the patch. But what’s not so nice about the patch is it doesn’t work as well. So it can increase your threshold. So if you took a bite of something and spit it out, maybe you won’t have a reaction, but it doesn’t let you eat a peanut. It does not let you eat the birthday cake at the birthday party.

It does not let you eat the Chinese food. And so again, it becomes a risk benefit. Like, is that amount of benefit enough for that patient that they want to do it? And again, these are all investigational therapies. So what is the UW doing to contribute to all of this? And so about in February of this year, we were awarded a clinical and research Center of Excellence. So UW is now on the map, you can see. So, I’m the director of the center. And so that means that we provide, it’s national recognition that we are a leading clinical center for food allergy. And it also means we are a participant in these investigational therapies that we’ve talked about. And that we’re performing cutting-edge research, some of which that I showed you today, about what causes food allergy, what are the immune mechanisms of food allergy. And so that’s really an exciting development for the UW that I’m really excited about.

So to summarize, food allergy is a failure of oral tolerance and it’s an immune-mediated reaction that occurs predictably and reliably on exposure to a food trigger. This is different than an intolerance. Food allergy is increasing in both children and adults in the U. S. and throughout the world. And we don’t really know why, but we think there are some key environmental exposures, such as oral exposure or bacterial exposures, or the microbiome that could be playing a role in this. There are no treatments. Families have to strictly avoid the food in all situations, and this significantly affects their quality of life. But there’s hope. Oral exposure can be protective, especially early in life, at least to peanut.

And we can maybe prevent food allergy. And as I highlighted, there are two therapies that are very close. We’re hoping for 2020 FDA approval. So with that, I’m gonna end. And this is a cartoon that was driven, Dr. Gupta, whose picture was on one of the early slides, this was one of her patients and she published it. And it’s basically showing the optimism in these food allergy patients. And so here’s the mom saying to the child, “When I was your age, there were no food allergies. ” So that’s what I say to my kids all the time, “When I was your age, there were no food allergies. ” And they’re all confused ’cause food allergy’s a part of their daily life.

And now my hope is, through the work going on right here at the UW, is that when that child grows up, they can say, “When I was your age, “there were food allergies. ” And now that child is all confused ’cause they don’t know what a food allergy is. So with that, thank you for your attention, and I’d be happy to take any questions. [audience applauding]