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My guest this week is Dr. Carrie Nadou. Carrie is the chair of the Department of Environmental Health at Harvard's School of Public Health, a professor of climate and population studies, and the interim director of the Center for Climate Health and the Global Environment. Carrie's research focuses on the study of immunologic mechanisms involved in the causes, diagnoses, and therapy for allergies and asthma.
Carrie earned her MD and PhD from Harvard Medical School in 1995, completing her doctoral work in biochemistry and immunology. She's a member of the National Academy of Medicine and has co-authored the book, The End of Food Allergy, the first program to prevent and reverse a 21st century epidemic.
In this episode, we talk about how the immune system works when it comes to fighting bacteria and viruses. Now, you might think, well, what does this have to do with food allergies? Well, of course, it's because the same immune system that correctly helps us fight off bacteria and viruses incorrectly gets wound up when it comes to food allergies. So unfortunately,
You do need to understand how the immune system works in the correct way to understand how it can go rogue. So from there, we deep dive into food allergies and we distinguish them from food sensitivity. So I think many people listening to this will have some sort of food sensitivity. And of course, that's also potentially mediated by parts of the immune system. We'll talk a little bit about that, but really what we want to focus on are true food allergies. And this can range from mildly inconvenient to outright life threatening and debilitating.
It's really that latter area that we want to focus on so we talk about early exposure we talk about what sort of immunotherapies are available. Many people for example listening to this will understand that there are certain people have peanut allergies if you have a peanut allergy and you don't carry an epi pen you can end up losing your life.
Well, I wanted to understand why that's happening. I want to understand what parents might be able to do to reduce the risk of that developing in their kids. And of course, for those who already suffer from those things, I want to understand what are the immune based therapies that can effectively take a person.
Who in the presence of even microscopic quantities of those allergens produce a lethal anaphylactic reaction and how can immunotherapy make those people safer in that presence and this is the kind of work that carry has been doing. And for that reason I've wanted to have carry on for some time. We also talk a little bit about air pollution which was a real bonus for this discussion for me.
Because when I reached out to Kerry initially, I thought we would only talk about food allergy. But as you may have heard me talk about on previous podcasts, I have a real interest in getting deeper down the rabbit hole of air pollution, specifically PM 2.5s. We go into all of that in this episode. So be sure to stick around for that part as well. So without further delay, please enjoy my conversation with Kerry. They do.
Kerry, thank you so much for joining me today. I don't remember the last time we were together in person, but I feel like it's been probably eight years or so. Is that possible? I think so. It's been eight years and losses happened, Peter, especially COVID. So it's nice to see you again. Yeah, yeah. I've always appreciated the amount of time you used to make for me when I used to wander into your lab at Stanford just to pick your brain.
Again, I've always thought that the work you were doing was so exciting. And I know that it ties into so much about what people are interested in around food allergies, even to some extent food sensitivities. And I think also even based on your current role, you've now left Stanford, you're at Harvard. I think it's also very interesting to discuss air pollution. I think this is probably something that isn't getting enough attention with respect to health. I know it's something I feel woefully deficient in my understanding.
Though I try to pay attention to my PM 2.5s. I'm not sure what to do with the information sometimes. So with all that said, let's maybe just give people a really quick background on why you're the person to be talking about this. So you're an MD PhD. What did your PhD dissertation focus on?
I was really excited to do my Ph.G. in biochemistry, so I learned a lot about toxicology and biochemistry, and I did my Ph.G. in parasitology, actually. I worked on an enzyme in a parasite called the tropanosome, which causes African sleeping sickness and another disease called Shaddaz disease.
And I loved my work there because we were able to go to the very minute levels of understanding of a chemical entity to be able to create a drug to target that entity to help people with that disease. So it was a great PhD. I loved it. And I also did that at Harvard under Chris Walsh. So that's what my PhD was in. And then I did other work in immunology and animal models as well.
And then you're a pediatrician by training clinically as well. What led you then to study the field that brought me to you as a matter of interest a decade ago around the field of food allergies.
It's all a build, Peter, and we think of our careers, all of these things mesh, but there are certain nexus points in our careers. And I believe that typically for me, it's been a patient and it's been an inspiration to be able to move forward in a field like food allergy. So I did my MD training also at Harvard, and then
trained in pediatrics at Children's Boston, as well as at Stanford. And with that, I had the opportunity to become a fellow in a field that I loved, which was allergy, asthma, and immunology. And I had done a lot of immunology work when I did my PhD in parasites, because parasites are killed by the immune cells.
And especially this little molecule called IgE that tends to kill parasites, but it's not so great for allergies. So this ying and yang of this molecule in biology as an immunologist for me was also really interesting.
Fast forward, I was a fellow on the wards and I was about to see a patient that I was being asked to consult on for milk allergy and he was in the ICU and I was told that he had just drank a cup of milk and had had a bad reaction. And by the time I arrived there, the unfortunate event of his death had already occurred. His parents were already being asked to give consent for him to be a liver donor.
And so I took care of the person that was the liver recipient who also had a milk allergy. That really gave me pause and number one inspired me and really initiated my efforts in food allergy to understand the role of this molecule called IgE, the role of the immune system,
how food allergies get started in the first place, how in the world did a child with food allergy who died, then give his same food allergy to the recipient of his liver. So all of these things really started to catalyze my curiosity and I felt very blessed and lucky at the time to be able to be in the lab
And when you're a person that has this training, I feel that we're obligated in a way to be able to use that training to best help mankind and to best help those questions that parents ask us. And so at the bedside of this particular young child that had died, unfortunately, did on milk allergy, I'll never forget his father, Trembling, asking why the EpiPen didn't work at the time.
What can we do to help children in the future never have to die again? And so I promised that father that I would do the absolute best to prevent further deaths in children and adults with food allergy, as well as help really make sure that we educate about the use of injectable epinephrine devices and how to best use them to prevent deaths.
to food allergies. So that's my why. And ever since then, I've always wanted to really help out in this field. It would be impossible, I think, for us to have this discussion at the level of depth that I hope we can have it without the listener understanding how the immune system works under normal circumstances. You've already alluded to one of the immunoglobulins, IgE. Does it make sense, you think, to talk about the family of the immunoglobulins, what they're there for, how we acquire them, and how they normally serve us well?
Sure. So we have certain proteins in our blood that help protect us. And that's what they're meant to do. And that's great. And they exist in different concentrations, just like in a milkshake, you have different proteins that exist in different concentrations. And they're all there for nourishment purposes, sometimes for taste too. But in our blood,
The proteins in our blood that constitute immunoglobulins are really helpful. We learned a lot about how important immunoglobulins were to protect against COVID, for example. Everyone wanted to know their, quote unquote, titers. And what that means is immunoglobulin. So the main class, IgG, immunoglobulin, those are very protective. Those are proteins that are in high amounts.
and they float in our plasma. And in order to be really healthy, when we are healthy, we have healthy amounts of immunoglobulin to protect us. The minute that someone is maybe what we call under a drug like steroids or under other drugs that could affect your immune system, that also reduces the amounts of these immunoglobulins. So we know that these immunoglobulins are really important. It's important to have good concentrations, not too high,
But good concentrations in immunoglobulins in general help protect us against infections, and they also help protect us against allergies.
Then there's another complimentary immunoglobulin suite that doesn't just stay in our blood. It also gets into our organs because you want to protect all of the surfaces around your organs as well, not just in your blood. The blood is great. That's the highway into so many organs, but it shouldn't be nice to have some immunoglobulin protective molecules that actually sit around your organs and help. So for example, that class is called IgA.
The other class was IgG, this class is IgA, and we call that the secretory class. And that's also helpful in our saliva, in our gut, especially women who are pregnant, they secrete it after pregnancy and their breast milk. So these are things that we've learned as immunologists that really help protect and enable health. When people are missing IgA, for example, if they don't make any IgA, they actually have allergies.
And the other immunoglobulin class that I'll talk about is called IgM. And IgM is what I call the Marines. That is the type of immunoglobulin cell, IgM, that goes out there first call. They're there to fight infections, but then the immunoglobulin G proteins come in afterwards and they stay for much longer. IgMs don't stay for very long.
The final class is IGE, so IGE, unfortunately in the past, when we were in the field and fighting animals and being out there in the wild, IGE was very hopeful to fight parasites, for example. It was very specific to parasites.
And now, unfortunately, IgE still exists in our blood. It represents 0.005% of all the immunoglobulins in our blood. So, of all those classes, the IgE is the least represented. It's the least concentrated, but it is unfortunately the most potent.
And I call it the match that lights the fire behind allergies. And you think, well, why do we have such a skewed response? Why do we still have this prehistoric molecule floating around in our blood that truly all of us consider a bad actor? And we think it's because of that prehistoric need to fight parasites. But importantly now, fast forward, thousands and millions of years, it's still there and it unfortunately has a skewed response in allergies.
So maybe just explain a little bit more about what the immunoglobulin does. Let's just talk about through the lens of an infection. So what happens when you get a bacterial infection and what happens when you get a viral infection? Those are two sort of different things, but yet they both kind of still involve immunoglobulins, even though we think of one of those threats, the viral illness being more dealt with through the cellular immune system versus the humeral. Maybe even you can explain what cellular versus humeral immunity mean.
So in general, what I'll explain today is how our immune system fights a virus or a bacteria or a fungi, but there's always some exceptions to the rule, but I'll just talk about the general pathway. And that, I think, helps people conceptualize what happens. And I'm always amazed at the immune system, and there's a lot we still don't know. So in all humility, as an immunologist, I learn every day what I don't know about the immune system.
But what we do know is that when something attacks us, like a virus, like a bacteria, like a fungi, that enters into our lungs, our gut, our nose, those unfortunate microbes, they know how to get into our body.
So, they get into our body and they go through either the skin or they go through other organs. And then on the other side is waiting for them a whole panoply of immune cells ready to attack.
And so if a virus gets in through the body, now typically it doesn't. We try to fight it right away, but sometimes it does. And so let's say a virus or a bacteria or a fungi gets into the body, gets through our typical
first layer like a skin barrier and it gets through. Then right away we have these cells called macrophages and they literally just eat up things. So they bind on to the virus or the bacteria or the fungi eat it up and then eat it up into small little bits.
And then they expose those small little bits on their surface. And then with those small little bits on the surface, they actually then become the educator pieces for another group of cells called the T-cell. And that's what we call the cellular system, macrophages.
antigen, presenting cells, these little bits are called antigens. And then the T cell comes along and says, huh, that's interesting. I'm going to teach myself the T cell. I'm going to teach myself how to operate within these little antigens. What are these things? How do I train the immune system to get rid of this thing?
So then the T cell says, all right, I'm going to start to understand what this new organism is that just attacked my body. And I want to fend against that. I don't want that bacteria or that fungi or that virus in this body. So the T cell becomes what we call a memory cell. A memory T cell then teaches another cell called the B cell. The T cell interacts with the B cell. The B cell then starts to make immunoglobulants.
And that BSO makes the immunoglobulins thanks for the teaching cell to train that BSO to make the immunoglobulins for the exact little antigens that that virus made or that bacteria made or that fungi made. So you have this little BSO. BSO makes these immunoglobulins and then they bind to the antigen.
Now you have specificity in your cellular and your humeral immune system. So the humeral comes from these antibodies that float in the blood, and that's what we call the humeral immune system. It's not attached to a cell, but it was made by a cell. So those humeral related antibodies attach to the antigen, and then another cell,
Again, back to that macrophage eating cell, that macrophage then recognized this whole system and we call it antibody dependent cell killing. So now that the antibody recognizes this virus and it recognizes all the viruses that maybe you had across your whole gut or across your whole lung for that one specific virus it recognizes as foreign.
And then these other cells called the macrophage come back again and they chew the whole virus up and eliminate it from your body. So that's a long system. I just talked about things that take days to respond to, months to respond to.
And it took many years of science to figure that whole pathway out. This is not something you learn at the bedside with some story your mom tells you. This is a lot of science. And that science has allowed us to understand the immune system to number one.
provide vaccines to people. Because of the same system, we now know how to make immunoglobulins because of our vaccines. And we know how long they can last for these memory T cells, for example, can last up to 100 years. So I love the cellular, humeral part of the immune system because it's very instructive to fight microbes.
Unfortunately, it doesn't fight all microbes. Some microbes need a little help with antibiotics, with antiviral. So the story that I showed you today isn't perfect. So that's why you need to see the doctor. You need to have other medicines, for example, to try to help your immune system fight infections, because there's holes in the immune system, and we need to help it.
Why do you think our immune system is on balance so much better at fighting viruses than bacteria, at least in terms of the clinically relevant ones? In other words, very few people will take an antiviral drug in their life outside of a handful of unusual circumstances. Most people will go through life with their immune system doing a very good job of lapping off the head of two to three viruses a year that actually reach the threshold of clinical significance.
And yet most people don't go more than two or three years without actually requiring an antibiotic to aid in the destruction of a bacteria. Do you have a sense even teleologically why that's the case?
This is an excellent question, theologically, as well as from an evolutionary point of view, as well as really understanding how did viruses start in the first place? How did a bacteria start in the first place? What do they need to grow? From the perspective of the virus, why do they need us? From the perspective of bacteria, why do they need us? Same thing for fungi.
So when you think about a virus, they kind of flit from one organism to the other. They sometimes can exist out in the wild. They don't necessarily need us. But sometimes, like HIV, it needs some of our cells to be able to live inside, to be able to keep proliferating.
So I'd say in general, there are some viruses that are, of course, very severe and they can cause fatal disease. So on the spectrum, like you said, Peter, typically though, viruses aren't as bad as bacteria.
We don't typically need an antiviral because we can fight viruses. It's a great question though because viruses can mutate in our body like we saw with COVID and then all of a sudden we can't fight them as well. But our body, because we make things like mucus,
that we have fevers, that we have these immune cells that are really programmed to attack quickly, they can chew up the viral proteins much better and much more easily to destroy a virus because a virus is really relatively speaking compared to a bacteria.
It's very simple. So it doesn't take a lot for the immune system to just say, listen, didn't take me a lot of energy to wipe that out because that virus is made out of simple things. It's basically made of really simple Lego blocks. But then you have the bacteria that's made of
an enormous amount of Lego blocks and it is much harder to destroy that. Same thing with fungi. They are much more complex organisms. They're made of many different materials so that it's harder for our immune system to kill every piece of the part and get rid of it.
So there are certain viruses, though, that we still get infected with, but that they don't cause fatalities. So they've learned to kind of use us and then move on because they want to just keep proliferating, but they don't necessarily stick around for our immune system to kill it. They just keep being contagious. So viruses are much easier at hopping from one person to the other, whereas bacteria
That's not so easy because they're heavier. It's harder to take a bacteria and give it to another human. With bacteria, I also think that we have this bi-modal relationship, and I want to make sure all your viewers know that there are some bacteria that are actually really good.
We don't know any viruses in particular that are actually good and beneficial for us, but our body lives with bacteria. So I think our immune system has a little tougher time to know, what is this? Is this a good bacteria or just a bad bacteria?
So that's maybe also why it's easier to kill viruses than bacteria. We've learned to be tolerant to certain bacteria, but not others. And some of them escape our immune system if they are bad bacteria because they know that we have this tolerance to other bacteria that are in the same class.
But it depends on where that bacteria is. It's totally fine if this bacteria is in your gut, but the minute it gets into your blood, if it's the same bacteria, it's actually really dangerous. So that's where our immune system has to figure out, is this a bacteria in the gut? I'm okay with that, or is this bacteria in the blood? I'm not okay with that. And bacteria tend to divide so fast, just like viruses, that for both virus and bacteria, these are difficult.
But when we talk about vaccines, we luckily have used science for both bacterially mediated diseases as well as viral mediated diseases. So it's really thanks to vaccines that we've enabled the immune system to get boosted for both types of infections. But it's always hard to predict mutants to predict different infections that one would have. But I think that your question is an excellent one. I don't have all the answers.
It's funny, I think there's an analogy there with cancer, which is what makes cancer so challenging for the immune system is that it's basically self, and it's very good at masking its non-self entities. So even though it's genetically distinct from a non-cancer cell,
It's very good at hiding the neo-antigens. Sometimes they're not even coding proteins. In other words, sometimes the mutation in the cancer cell doesn't lead to the generation of an antigen and therefore it can go completely undetected, masquerading itself.
Exactly. And that's the sad part about cancer, that our memory T cells that are supposed to be there to protect us and monitor and make sure that any cancer cells could be killed right away, sometimes it's faked out in a way. And that's where I think the CAR T cell therapy, a lot of the T cell mediated, immune mediated therapies now can enable
and better instruct our immune system, but that's not perfect either. So you're absolutely right, Peter. This yang and yang of having the immune system do all that it can, but we can't expect so much. And one of those areas in order to help our immune system, we found in COVID, for example, people that slept better, people that ate a healthy diet, people that exercised in general, their immune system was healthier.
So I think when we talk about these public health issues and COVID kind of was the x-ray into our soul of public health and public health processes, but in that we learned a lot about what it takes to be healthy and what it takes to have a healthy immune system to better fight viruses and microbes.
I'd like to actually come back to that because it's such an interesting topic. It's one of those things where it seems obvious and self-evident that all of those things are true. I think I would also add stress to that. I think it's hard to understate the harm that hyper-cortisolemia and are ramped up sympathetic system to have in the immune system. If we have time, I'd like to come back to that and probe a little bit about what the mechanisms are for that.
But what I really want to get to is now pivoting to this idea of what a food allergy is. And I think it would maybe be a good idea to differentiate between a food sensitivity and an allergy. Is that the right terminology that you would use?
Yeah, that's excellent. So for a lot of my patients, this comes up all the time. And I am inspired by how much knowledge my patients have. They come to the table or they don't come to the table with knowledge already that they receive from the internet or podcasts such as yours and others, as well as just reading in general. And finally, asking questions is so important.
If you don't know something, feel free to ask your doctor these questions. This is critical or a healthcare provider or anyone. But I've always been really interested in this difference between food sensitivity and food allergy. So food sensitivity means that you can bite a food
And you're typically going to react to a chemical in that food. Perhaps a protein, but it's mostly a small molecule. Maybe a sugar, maybe a fat, maybe a spice. And with that, people can get headaches, people can get bloating.
Typical food sensitivity is lactose intolerance. When you drink milk, for example, one of the sugars in the milk is called lactose. And if you don't have an enzyme in your gut and in your body called lactase, you can't break down that sugar.
And so that's why people take lactate milk, for example. And there are some ethnicities that don't have that enzyme. So there is a bunch of people that in a certain population really can't drink cow's milk because of that lactose sugar. So that's a food sensitivity. People get bloating, people get headaches, but they're not going to have a fatal reaction. And just to be clear, Carrie, the immune system is not reacting at all in that state of a food sensitivity.
It can react with you have enough lactose and you keep drinking lactose and your body says, I don't like the sugar. Why are you keeping giving me the sugar? I can't break it down. What happens is it sends its immune cells to try to break it down. And that causes inflammation.
So some people when they take preservatives as well as certain emulsifiers, these chemicals, they can get into the body and our immune system doesn't like it. It's foreign. A lot of our preservatives and unfortunate emulsifiers that hasn't been seen by the body before, it's not something that's natural. So for some people their immune system does react, but it reacts with a different pathway than an allergic pathway.
It reacts with sometimes immunoglobulins. IgGs, it reacts with something called a cytokine that isn't great because it causes chronic inflammation. So we do have some chemicals that are associated with food sensitivities that can activate the immune system.
in a way that's not great for the human body. And so that's why if someone does have bloating or headaches or they can still have rashes for food sensitivity, you can still have rashes in your skin with certain chemicals that you eat in foods. And if that's happening to you, then get yourself tested because we want to make sure it's not a food allergy.
But importantly, as we don't have cures or therapy for food sensitivities, we often will tell people, please avoid that food. The guy has someone that has terrible bloating with mushrooms because there's a certain chemical in the mushroom that bothers her immune system. Why? I don't know. But the minute she even smells the mushroom, she gets this immediate reaction to her gut that causes her to vomit, but it's not a food allergy.
It's an intense reaction of the nervous system to that food chemical.
Sometimes we see people who have kind of a low grade elevation of their C-reactive protein. And we really like to see the very sensitive version of that below one. You'll see these people that otherwise seem reasonable, but their C-reactive protein is somewhere between two and three. So it's two to three times higher than it should be. And it lingers in this state for a very long period of time. There's clearly no infection that's been brewing for that long.
You query them a little bit more and you sort of realize that it might be attributed to food. And I would say in my experience, the two foods that far and away account for the majority of this as determined by simple elimination and watching this go away are first, wheat related products and secondly, dairy.
So when I say wheat, I don't mean celiac disease, which I'd like you to explain as a contrast, but rather some sort of low-grade sensitivity. And so what you're saying is there is nothing going on in the IgE pathway, but there is something going on in the IgG pathway. And again, C-reactive protein is made by the liver as basically a calling sign to the immune system. You're sort of seeing, for lack of a better word, you're seeing the sirens going constantly, which is CRP.
We can measure what we can measure. And CRP has been around in our doctor's handbag for a while. And it's actually a really good beacon like you analogized because it does tell us something's going on there. And it is a window into what's going on chronically in the immune system. So yes, when I test the CRP levels in my patients with food sensitivities and they're not able to eliminate that specific chemical,
then I see the CRP in that range where I call it simmering immune inflammation. It's not a fire, but it's simmering. And the problem with food sense to these is I don't have a great way to diagnose them. I don't have a skin test. I don't have an IgE test. I have to do elimination. And then I follow that CRP level until it can try to get to zero. But that's not easy because some of these chemicals are so systematically in our food supply that it's hard to get rid of. So that's
food sensitivity. And I agree with you, milk and wheat are some of the most associated culprits in food sensitivities, especially in the US. And that might be for a lot of different reasons in terms of how we process and how we have detergents in our milk and the same thing with our wheat products. It isn't necessarily the same wheat that we ate when our ancestors ate it originally.
So maybe there's a lot of reasons for that. But let me bring it to wheat. This triangulation of food sensitivity, celiac versus food allergy, and we'll get to food allergy. But let me just transpose this interesting comment you made about food sensitivity versus celiac. So celiac is a very specific type of food sensitivity.
And it has a very marched out pathway of immune reaction to that wheat, and that wheat protein, and specifically is the gliadin, which is a part of the wheat. And celiac disease also has genetics associated with it, and other autoimmune disease with it, as you know. But that reaction is to a very specific part of the protein of the wheat, and not everyone with a food sensitivity wheat has celiac.
And certainly not everyone with celiac will have the same type of reactions to wheat as the food sensitivity people do. Now, celiac we take extremely seriously because it can result in long-term problems with your gut. It has its own special category, but you shouldn't call yourself someone that has celiac.
just because you have a food sensitivity to eat. There's a specific diagnosis that needs to occur with a professional that specializes in gastroenterology or in celiac to be able to know if I truly have celiac disease. And if you do, then it's important to test family members and to really get under the care of a good doctor.
Are we seeing any increase in the prevalence of celiac disease or are we seeing any increase in the prevalence of food sensitivities? It certainly seems like it as a nonepidemiologist who pays attention only to the world around him, but it seems like more and more people are saying, boy, I'm really struggling to eat. Fill in the blank.
On one side, I think that people are becoming more knowledgeable about this, and they also feel they have agency as they should when they come to the doctor to be able to say, I think I have a sense to me this food. And people take them seriously, and that's good. And we need that because these symptoms are serious. They're affecting someone's quality of life. We need to help.
And in the past, maybe they were poo-pooed and said, oh, I can't help you, so I can't do anything about that. But now, people like you and I can say, well, let's test that CRP. Let's see if we can be better detectives and really try to help you. Because in the end, we want to help quality of life.
So yes, people I think are feeling more and more like they can talk about it as well as celiac disease. But importantly, is we have better diagnostics. So I think that we as a community have gotten better at really diagnosing celiac. So I think that's another good reason why there might be more people with it.
I think people also are seeing an increase in food sensitivities in celiac because of the different ways that weed is processed, because of the different detergents now and unfortunate chemicals that are put into our foods. So I think we have to be careful about that and hopefully the food industry and agriculture will think carefully about those chemicals before they put them in because I've seen an increase. And when I tell people to not eat foods with those chemicals in them, they tend to not have
food sensitivities. So I think that perhaps, and I'll be interested in your comment to Peter, that might be one of the reasons why there's more food sensitivity, although I can't put my finger on it.
I feel like there's something going on and I know we're going to talk about this also on the food allergy side where I think we can probably speak with more clarity. Let's not talk about that because I think this is the area where let's just start with some statistics. Do you have a sense of how many people in the United States die in a year as a result of a food allergy like the tragic story you told?
Yeah, thankfully it is extremely rare. The reason why I hedged is because nowadays with the codes in the emergency rooms and understanding if someone died from a food allergy, some emergency room, some intensive care units, they're able to ascribe or attribute a certain reaction exactly to a food. Sometimes it's a little blurry.
So it is very rare. There are people around the country in Michigan as well as in Chicago that are epidemiologists. I am not an epidemiologist, although I love to work with epidemiologists. So it is very rare. People have claimed that it's
One of the reasons why people can have a fatal attack is because they don't have access to an epi device where they don't have anticipatory guidance for what to do during a reaction. So in my mind, any fatal reaction could have been avoided. And that's why I learned from that case, even though the fatal reactions are rare and that's good.
they could be avoided. And when we learn about them, and I learn about one per month in the US, and it's very sad. Every one of those stories comes with a tragedy that's heart wrenching, but it compels me to keep trading my patients on making sure they have two injectable epinephrine devices at all times, making sure they know how to use it within a minute, making sure that if it doesn't help their symptoms within a minute, that they use another.
right away, that it's okay to use an injectable epinephrine device because that's the only thing that can actually prevent the unfortunate death. And so I think the numbers right now in terms of death rates are getting lower, which is good, because people are understanding more about this disease and the communities understand that why we don't want to expose people unnecessarily to foods that could kill them.
But in addition, there are increasing incidence and prevalence of food allergies in general in the US. So, for example, my colleague, Ruchi Gupta, out of Chicago, she published data that one in every 12 children in the classroom in the US has a doctor's diagnosis of food allergy.
And we used to think that children would lose their food allergy, especially those with milk and egg. So it used to be thought even when I was training that children with milk and egg allergies, if they were under the age of five, there was like an 80% chance that they would lose these allergies by the time they were teenagers. But if it was peanut or any kind of tree nut or shrimp or fish, they had an 80% chance of keeping it.
Now, unfortunately, if you have a milk or an egg allergy and you're under the age of five, you have a 50% chance of losing it. So now we see more and more adults having food allergy. And the other unfortunate thing, Peter, is that more adults, when they get to adulthood, are getting food allergies.
That's presumably about one in 30 adults will have some type of food allergy when they're an adult, whether or not that's because they had it when they were children or because they gain it newly when they're an adult.
So the numbers are rising. Luckily, the death numbers are not, but someone needs to do more research on that. But this compels me as a food allergist to really make sure that both children and adults understand this disease and how to manage it. So let's talk about how this occurs. Unless it varies by food, can we just pick a very specific example like a peanut?
That's great. We talk about peanuts in the US, Peter. I also want to get back to your original question about the incidence and prevalence of food allergy. It's occurring throughout the world. It's not just a US problem. So peanut is also not just a US problem. It's the UK and Australia. But not in Italy, for example. In Italy, hazelnut is number one in terms of the sheets. In Japan, it's fish. In China, it's milk.
So we can talk about peanut today because it's an example of how our immune system reacts to something, but it's a very similar immune reaction to a child in Japan who has fish allergy or a child in China who has milk allergy or an adult in Italy who has hazelnut allergy.
I've seen a spectrum of allergies. I've seen people that have allergies to cinnamon. I've seen people that have allergies to orange pit seeds. All of these have proteins in them. So people can actually become allergic to these proteins. People have allergies to the tannin proteins from grapes in wine. So I'll tell about the story of the peanut, but I want people to know that it's not just about peanuts. And many people that have allergies to one food have allergies to other foods.
So people also need to know that if they have a child with a food allergy, expect that it's highly likely that that child will develop another food allergy as well. So be super careful, but also super vigilant about taking your child or yourself to the doctor to keep on getting managed and diagnosed.
So, you have a peanut, and we think that one of the reasons why people start to have food allergies is not genetic. 70% to 80% of the time, it's environmentally related. It's not related to genes in the family.
So when a baby is born, perhaps their skin is a little rough and a little dry. And there might be microscopic holes in that skin. And that happens a lot now. A lot of children have dry skin and we can talk about that another time. But with that little dry skin, that means the cells, my two hands here are cells called epithelial cells. Their skin cells that typically are connected with a nice, beautiful barrier.
But unfortunately, the dry skin, they kind of separate. And our body doesn't know how to deal with this separation too well. It thinks it's like a mosquito bite. It's like, what the heck's happening? I have a little hole in there. And so it reacts to these types of holes as if it was a mosquito bite.
So all of a sudden in the air, you have dust that might contain hazelnut protein, or in this case, peanut protein. And that comes settling in and it goes through this hole. And our body has a very prehistoric way of dealing with this back to those parasites. So it comes in.
by just passive aeration. It drops down the skin. The body tries to pick it up and it tries to sense this just like I explained in terms of the immune system. Those macrophages are like, what the heck is this? Is this good or bad? And then it says, wait, this is bad.
I'm not supposed to have food through my skin. I'm supposed to have food through my gut. So the cell takes it up and activates the allergic pathway because it thinks it's a parasite. It thinks it's a mosquito bite. So what happens is it takes it up and makes this molecule called IgE from that B cell. So the food gets taken up, gets processed,
It teaches a T cell to interact with that food antigen and then the B cell starts to make IgE against that very same food antigen. So the next time that baby eats that peanut, even if it eats it through the gut, that little IgE molecule will have been made by the B cell and it's sitting around in the blood and then it will bind to the peanut protein that the baby eats.
And when it does, even though, like I said before, the IgE is a very small percentage of the concentration of proteins in the blood, it is such a potent molecule. And what I call it, it's the match that lights the fire behind allergies. So you have this peanut that otherwise, for you and me, Peter, we would be able to eat and we view it as nutritious. But in a person with an already given allergic reaction to peanut,
That IgE binds to the peanut, and then this part of the IgE molecule, my arm, that sets into another part of a cell.
as a receptor. So it docks into the receptor after it binds to the peanut. And then that receptor on the cell surface activates histamine release of the cell. And that occurs within minutes. So the histamine goes through the body and within six minutes causes
swelling can cause mucus, and that mucus can be in your lungs, can be in your eyes, can be in your nose. And it also releases histamine, that cell releases histamine, and that histamine because itching on your skin. Very similar to what would happen if you got a mosquito bite, you want to itch, you want to get rid of that mosquito in the same way the body's trying to get rid of that food. But unfortunately, you've already eaten it. It's already in your body.
And so you see these reactions via IgE, and they release histamines. And in my mind, it's a very skewed reaction. The body's trying to do something that it was meant to do prehistoricly, but it doesn't help the person at all. In fact, the histamine becomes so high that it can cause sometimes death.
And within minutes, if you already have asthma, if you already have lung issues, that mucus can become so strong that it clogs up your lungs, and that's what oftentimes can lead to those very rare fatal reactions. Or there's another chemical called bradykinin that is released by these cells once that receptor docks.
When the IgE docks into the receptor, once that receptor tells the cell to release, it releases histamine and it releases something called bradykinin. That's another bad act or chemical. The bradykinin can affect our blood pressure system that can lead to dizziness and can lead to heart issues. That's the second reason why people have fatal reactions.
So you can imagine when you take epinephrine through an inductible epinephrine device, that helps both the lung, clear the mucus, and it helps the heart and the blood pressure stay strong so that you don't have one of these near fatal or fatal reactions. But it all is linked to the immune system and how it reacts, and it's a very fast reaction. Is my memory correct that the cell that's releasing the histamine is a mast cell? Am I remembering that?
Good, I was hoping you'd ask that. So again, you're seeing both sides of the story for the immune system, the humeral response, which is IgE, and now the cellular response. So once that receptor gets docked into by the IgE,
The cells that have that specific receptor on them are called mast cells. They're also called eosinophils. And for those of you who are listening, there's another type of disorder called eosinophilic disorders, which that's a different type of food allergy, but also related. And then those mast cells exist in tissues, but they're not in the blood.
Eosinophils are in the blood. The other third type of cell is called the basal cell. That's in the blood. So this is such a potent system because it's got these cells ready to go. In the tissues, the mast cells, the mast cells are in the skin, they're in the gut, they're in the lung, in the eyes, in the nose. And then you also have these other cells floating around the blood that are also
secreting histamine and bradokinin. They're like the messengers across the whole system and then you have the mast cells embedded and the mast cells can live a very long time in tissues. So these basophils and eosinophils are in the blood. These mast cells can live a long time in the tissues and that's why someone's reactions can build up over time sometimes because every time they eat that food or have that allergen exposure, their mast cells are going to remember because of the immunoglobulins that bind to them.
Is the implication carry that each successive exposure gets worse? As a follow up to that question, how often is a person's first brush with a food allergy, a fatal one?
So we're only as good as our data. We're only as good as epidemiological studies as well. So typically, and this is again typical, there's always exceptions. If you learn about your allergies before the age of two, those food allergic reactions are typically vomiting and hives. They're not typically related to lung and heart. So babies, for example, although there are rare exceptions, toddlers and babies typically do not have
fatal reactions to their first ingestion of food. But there's a lot behind this. So if you actually dissect out who dies and who doesn't die from a food allergy, it's typically people that already have a heart problem, already have a lung problem, or didn't get to the EpiPen fast enough. So it would seem logical like you're inferring that with every dose that you take, your reaction could get worse and worse with the same dose.
But it depends. It depends, for example, if you're at elevation. It depends if you already have a cold. It depends if you have aero allergies and you're allergic to a dog and a dog came by you that week and you also ate a peanut.
So there's a lot that change that, but yes, in general, if all things being equal, each time you ate it, your immune system would remember more and more and will boost up that response. Now, luckily with therapy, there's a way to retrain your immune system, but that takes regular interaction with the food every day. Not every week. If you take it every week, it actually boosts your immune system to become more allergic.
Take it every day. So there's something to the circadian rhythm and the diurnal cycle which we haven't talked about this yet. But what I love about the immune system is it can be trained and you just need to know how to train it and you can train it away from becoming allergic and train it into becoming more protective.
I absolutely want to focus on that because it's I think the most hopeful aspect of all of this, but I want to kind of go back and understand more these environmental factors that are predisposing children and adults to these factors. So you mentioned one, which was dry skin.
I can only imagine after listening to this, everyone is going to be lathering up themselves and their children. And we're going to make L'Oreal or whoever makes nice skin lotion. Very, very happy. Are there any other factors that we've identified that seem to be predisposing people?
And there's some factors if they're lacking, they also predispose people. So people have talked about having good microbiome, good dirt, and that helps decrease the likelihood of food allergies. Children who grow up on farms, for example, have a really good exposure to animals. They tend not to have as many food allergies, interestingly enough, so I call that the dirt hypothesis. Also growing up with a lot of animals like dogs also helps reduce the likelihood, and that's probably due to the microbiome.
But importantly, as vitamin D seems to also play a role. So having enough vitamin D in your blood also decreases the risk of food allergies. Being around too much detergents, that's what I call the dry skin hypothesis. Unfortunately, a lot of our clothing being washed and detergents are dishwashers having really potent constant detergents these days.
It's not getting rinsed away enough so that the skin and babies, it heals so well, but it is somewhat more sensitive than, let's say, adult skin. And so because of that, they tend to have dry skin due to all these other issues and let alone detergents, but also any time in life, whether or not you're a child or a baby or an adult,
If you have pollution or tobacco smoke, that also causes dry skin and itchiness and not just the skin on the surface, but also in your bodies. Anything that touches the air has skin cells. So that means our lungs, that means our gut. So all of these features that I talked about can affect the skin.
We think that through the skin allergies can begin. It's not the only hypothesis. We also think that it's really important to make sure that when you look at your overall diet that you diversify that diet really early and often so that if you can take certain proteins and feed that to your children when they're young and have that diversity in the diet that that can actually prevent
the advent of food allergies later on in life. So we talked about dirt, we talked about dogs, we talked about detergents, we talked about vitamin D, and we talked about diversity in diet. So I call that the D's. But importantly, that dry skin does seem to be a conduit by which food allergies start.
But what I didn't say was DNA. And that's important because a lot of parents, a lot of people will say, oh, my parents gave this to me. Or this is in my gene, so there's no way I can do anything about that. And that's not true. So there are certain allergies that can be passed on from one generation to the next. But even those diseases, if you change your behaviors,
That can also improve and decrease the likelihood of having food allergies. So I hope that was helpful. When people do listen, I hope when they do try to improve their skin barrier, if there is an emollient you can buy, try to stay away from the emollients that are based with petroleum products or paraffin products.
or Vaseline, because what science has now shown us is that because those are not natural to the skin, our skin doesn't really like wax or petroleum products. Vaseline is a petroleum product. That tends to increase the bacteria on our skin, and that can make overall the skin inflammation worse. So try to choose products that have natural lipids that give the skin back what they're missing.
How does one look for that on the label? What would be the signs of that? The natural lipids are like ceramide. So I don't work for any companies. I don't really know which companies have ceramide, but I know one company, Sareva, has ceramide in it. So try to look for those emollients that actually replete the skin with what it is depleted from, which are its natural lipids.
And then also try to rinse things. Now we are in a water shortage and we have to be careful too with not using too much water. But if you can choose ecologically friendly detergents because eco-friendly detergents, eco-friendly foods tend to be better for our own bodies. And I'd love to know your own opinion about that, Peter, but that's what I typically tell my patients. Try to avoid detergents that are not eco-friendly because they're probably not so friendly to your body.
One of the question about this, any relationship with breastfeeding, you mentioned it earlier with respect to IgA, does a child who's breastfed or not breastfed? Do we see any difference in the incidence of food allergies?
There have been a lot of my colleagues in Europe that have tested this. Now, because breastfeeding is now so much the standard that it's hard to do these studies now, because the World Health Organization has recommended breastfeeding, which is wonderful, and that's really important to start feeding infants other types of foods between four to six months of age. But in general, breastfed infants do do better in terms of their overall gut health, in terms of their overall health in general.
But it has not been shown definitively that by breastfeeding you can prevent food allergies. But it is very helpful towards creating an overall healthy immune system. So I, in general, tell all my families if you can breastfeed, please do.
But the ulterior unfortunately is that some children, it's very rare, but they can have an allergy to a protein in the mom's breast milk. So if your child does start to have issues with your breastfeeding, go see a doctor and then see and make sure that they don't have an allergy to your own milk. But that's very, very rare.
And nowhere in that discussion of the Ds, did I hear, I guess you talked about diversity of diet, but I want to talk specifically about the antigen. So what is the case for and against early exposure to nuts as a vehicle to prevent the onset of one of these allergies? I think about the last 15 years, I feel like I've heard pediatricians go
in various directions on this. At first, it was, and I think about the student lens of my kids. So it's like, sometimes we were told, absolutely don't let them see a nut. Don't have nuts in the house for the first two years to, hey, make sure they're eating nuts and peanut butter. So where are we today on that?
I agree, Peter, it's been confusing. There's been a lot of flip-flopping, and unfortunately there were well-meaning people 20 years ago that made guidelines based on not a lot of data. I think that people were seeing there was an increase in food allergy throughout the world, and that's probably due to many different things, but they reacted.
in a way to say, oh, we don't have enough science, but we're really worried. So let's just tell people to avoid those foods. And hopefully that can prevent this epidemic from increasing. And unfortunately, the minute those guidelines came forward, and it was also during the time that I was raising my kids, the minute those guidelines came forward, you started seeing a hockey stick in the epidemic. It actually started to increase in those countries that did not follow those guidelines.
It's state front. That's a very telling case, even though it's not a randomized intervention, that says when you avoid foods at a young age, you paradoxically predispose to the allergy.
Exactly, so let's talk about that. The importance of guidelines, I agree, they're very important and oftentimes guidelines are made by people that really think hard and they use the data that's at hand, but we're only as good as our data. So, fast forward, 20 years afterwards, the world had different data.
The world said, wait a minute. We now think that through the skin, allergies begin. Through the diet, allergies can stay quiet. We now know that the gut is really important for tolerizing to those antigens. The immune system in the gut is meant to tolerize. The immune system in the skin, in our lungs and in our skin skin, is actually meant to be activated and react.
So when you think about that dry skin hypothesis, of course, it's going to be promotional of allergic pathways. But when you think about taking things for the gut, it's going to be promotional of tolerogenic pathways. So we learned a lot in the last 20 years. So when the same people came together and wrote the guidelines 20 years afterwards, they said, wait a minute, it's very clear now. And many guidelines have changed, Peter, now to say, we need to diversify the diet. We need to tell our country's population
to start having children eat foods in small amounts like tree nuts, like fish, like milk, like egg, like peanut, and to be able to have that early and often and regularly so that we can try to prevent food allergies. So that's the general mantra. The guidelines have now switched. Same thing for people who are pregnant. It used to be thought, women who are pregnant, based on a
very small study, only 20 individuals, but that was the only study that was available 20 years ago that those pregnant women should avoid peanuts and tree nuts, but actually fast forward 20 years after there was a much bigger study done, and that showed that definitively it's okay to have peanuts and tree nuts when you're pregnant. It's actually healthier with omega-3s.
Of course, people who already have food allergies shouldn't be eating these foods when you're pregnant or if you're a child. But in general, it's a way to prevent food allergies now, among many other things like we talked about. But it does seem to be important, and it goes back to those instrumental recipes of the immune system. If the immune system can probe the antigen, know that it's safe, know that it's not going to harm the immune system or the body, it then becomes tolerant.
But in order to give it that instruction sheet, in order to give it that recipe, you need to feed and you need to get exposed regularly. And we think regularly means every day to every other day. And you'd say, well, wait a minute, why? My grandmother didn't have to feed me these foods or my mother didn't have to feed me these foods regularly. What all of a sudden changed?
And we think that the environment is changing. We know the environment is changing all around us. Unfortunately, with different detergents, with different emulsifiers, with different chemicals in our food, with different pollutants, with different viruses, it's changing. So now we take the science and we have a better instruction sheet for patients, and I'm grateful for that, but it is all based on evidence.
Do you think the genie ever gets back in the bottle? Do we ever get back to the levels we had 30 years ago? Or do you think that even if we can get dietary practices to where we were, which is to say we're at a place where parents are encouraged to liberally and diversely sample food for their kids, these environmental issues, the detergents, the dryness of skin, all those things, the low vitamin D, presumably because kids are playing outside less these days and they're
endures more and all of the things that we understand that it never quite gets back to the level it was when I was like, I gotta tell you, when I was a kid, I did not know another child that had a food allergy. All through grade school, middle school, high school, there was not another child in my zip code that had a food allergy. Today, my kids can't take nuts to school. You can't have nuts on an airplane today. So I can't tell how much of this is overreaction. There's clearly a log full change.
But I can't tell how much of it is also just a disease of the brain, if that makes sense.
No, but you're right to ask that. And lots of epidemiologists have now tested it. It's real. I mean, this is not just people thinking they have allergies. And when you and I are growing up, they didn't. This is real. There were people very rarely that had a milk allergy, peanut allergy, but the allergist never really focused on them. Now, the typical allergist, and we have allergists that have worked in the community for 80 years,
Their offices have shifted from being offices where aero allergens were what they took care of all the time, to now it's foods. And that's not because someone thinks that they're alert to food. This is a real diagnosed food allergy. And I think
Your question is a good one, but I don't think we're ever going to get back to 30 years prior because we have different practices where we have different ways of processing food, different environmental exposures. Because this is mostly environment, if I have identical twins born to the same mom and dad, I can have one twin develop a food allergy and the other one doesn't. And typically that's an adulthood.
And the one twin that develops a food allergy, they're the ones that have been out in pollution more. They've eaten not such a healthy diet. They have a lot of preservatives or they smoke or they eat a lot of fast food or they are under a lot of stress and they don't get a lot of sleep. So genetics being equal, exposures in early life being equal, there are certain behaviors that now we're seeing are more associated with food allergy like air pollution.
I don't think we'll ever go back, but luckily science has helped us so that we know what to do now and how to change our behavior so that we can try to prevent food allergies from worsening.
So let's now talk about the work that you've been, well, I'd like you to put the context around your role. I mean, of course, I think of you as pioneering this work. I'm sure you'll elucidate us all with how many people are pioneering this work. But you and I met, like I said, about a decade ago through a mutual patient of mine who at the time was being treated by you. Quite frankly, I was just sort of blown away.
at the fact that a person who once had an anaphylactic reaction to nuts was going through an immunotherapy-based sensitization program with you at Stanford, and then all of a sudden didn't have an anaphylactic reaction to nuts. This was mind-boggling to me, and I'm forever in your debt for graciously letting me wander around your lab and sitting around chatting with me over coffee. So can you give us a bit of a sense of
what this revolution is about. It's sort of hard to wrap our head around when you consider the lethality of these conditions. We take this so seriously and that particular family has been so engaged like so many other families that this is a disabling disease. My colleague Kim Yates has done so much work in this series as well as other families to be able to educate and organizations like FAAR and others have really moved the needle forward.
So when you think about food allergies, it becomes in a child's mind or an adult's mind something they have to live with and it's not fun and it can affect their social lives or quality of life. So they come to the table often wanting to know what's the best therapy now. And compared to when we started with your patient, we have a lot more therapeutic options and that's always good in any field to have options.
especially for our patients. So any of these decisions that I'll talk about today, they're really personal. They're really something that the doctor, the healthcare provider should talk to the patient about and see what's the best for me. But in general, again, getting back to that immune system, getting back to the regular eating of foods so that you can start retraining it to tolerance to those foods, to see them as natural and not unnatural.
This has been going on for about 100 years. And even though to us and to many others, this is something new, and we did work at Stanford, but actually other work at other institutions in the country and other work in Europe had already been done. So what I was doing is building upon
other evidence and clinical trials that had been done. And I worked very closely with the Food and Drug Administration, the FDA, because you don't want to do anything that's not safe and that you wouldn't want to do for your own children if they had the disease. So with that in mind, I learned a lot about the immune system.
What you do in immunotherapy at the very basic level is give the person back the very same thing that they're allergic to. And this was done 100 years ago with dog allergies, with cat allergies, with grass allergies, with mold allergies. People would actually start to take these things but inject them. A lot of your patients might have done allergy shots when they were little.
But those are ways that we've learned as immunologists that, oh, you can retrain the immune system. You can train a body so that they are no longer allergic to cats, for example. But you need to keep taking those allergy shots in general. So the same thing for food. You don't want to give a food allergy shot because the food in and of itself is very potent.
And because it's a very specific IgE-mediated disease, foods, if injected into you, can be extremely dangerous. So we don't give it via injections. Just to be clear, the allergy example, let's say it's cat, dander, or whatever, is the shot giving you a little bit of that dander? Is it sensitizing to you a little bit? And how frequently does the patient need that to achieve the symptom-free existence?
Initially, you need to take it almost daily, daily to a week. And then once your body starts to build up that immune muscle, you only need to take it about once a month. But you will do that for life. Well, some people do it for life. Some people do it for five years. If you stop it after five years, you have a 25% chance of regaining your allergy. Another 25% chance of having it just be less, but there,
And then you have a 50% chance of having it be resolved for the rest of your life, but you need to be on five years of immunotherapy depending upon the arrow allergen. We're talking environmental allergies. Yeah. And is the reason that you can get away with doing that because it does not induce anaphylaxis in the way that the food does? So it's just the severity of the IgE mass cell reaction.
Exactly. And we still are trying to understand why that is. Why is grass allergy not as bad as peanut allergy? So people are still trying to figure that out. Why is dog allergy not as bad as peanut allergy? But given that it is,
For immunotherapy, like we said, you give small amounts of that specific allergen back to the patient, whether or not it be a shot for environmental allergies or whether or not it be orally for a food allergy. You give it back in small amounts. You start with a small spec that you can hardly see, and then you increase that dose by 25% every two weeks, but you're giving it every day.
And then you increase it step by step. Every two weeks, you increase the dose, but you're giving it daily. And you want to do that in a doctor's office. You want to be really careful about that. So we did it in our clinical trials. Over time, you readjust the immune system. Now it takes a while, right? This person has had their allergy and it's been quite severe for them. So to retrain the embedded memory aspect of the immune system takes time. And what happens over time in the immune system is
Those little T cells start to be taught that, oh, wait a minute. This antigen, it seems okay. I'm getting it every day. Boy, I need to readjust myself. I need to reframe my mindset. And instead, T cells start to reframe their mindset. You start creating another whole layer of memory T cells that become tolerant to that antigen. And then they teach the B cell,
to forget making IgE. In fact, we want you to make more IgA. We want the B cell to make more IgG because that's protective. And so that's what happens over time. During the first year of immunotherapy, you're slowly going up, you're slowly readjusting. And in our patient's case, that's exactly what happened. That person was readjusting their immune system, readjusting their immune muscle to then switch from an IgE mediated
bad reaction to instead creating protective molecules that could protect the patient against the allergy. The IgE can still be there, but you have this huge amount of protective, what I'm going to call, blanket, so that that IgE doesn't have anywhere to go. When it wants to bind to the receptor, that blanket of immunoglobulins don't allow it to bind to the receptor.
We all have IGE, all of us do, but some of it works and some of it doesn't. In the case of the person with the anaphylactic reaction to peanuts, do they ever go above the 0.005% IGE concentration? How high does it go just for comparison?
IgE is typically specific. You have to have an IgE to a specific food to be able to have that reaction. And yes, typically some people with peanut allergies will be over that .005% or anyone with allergies. Their IgE is higher. And just so you know, a virus can also increase IgE, non-specifically. Your body just starts making IgE probably against the virus.
It's a very prehistoric type of reaction. But importantly, Peter, for every IgE molecule, we can make 100 IgG molecules that protect against that IgE molecule circulating and becoming potent. And that's what's happening during the time of immunotherapy. You're making a huge amount of IgG molecules to bind against that IgE becoming what I call pathological.
So it's a ratio thing. Just give me a sense of scale. So on the very first cycle, that first two week cycle, what fraction of a peanut is being given in the capsule? How small is it? I'm sure it's less than a single peanut, obviously.
Yeah, it's about 1-200th of a peanut. You start very low and you go very slow because in the end, you want to retrain that immune system, but you don't want
to activate it too much. Now during that retraining, sometimes your muscles get sore, right? Sometimes you will see some hives. Sometimes you will get a little itchy throat. Your body will have these little reactions, but I call them simmering reactions, but you do need to take it every day. And then you start to see the switch from IgE to IgG. And again, the T cells are responsible for that. Many other cells are too. But in general, if you stop the therapy,
This beautiful pathway of tolerance then starts to go back to the original pathway. So it's really protection. It's very rare that a person completely flips and becomes not allergic. Does that make sense? It's really what you're doing in the immunotherapy is changing your threshold and creating more protection molecules around you and creating more protective cells around you. And when does that switch flip?
If you're on the typical immunotherapy regimen, it flips it around nine months to a year. Again, just to give people a context of the doses we're talking about, someone comes in with an allergic reaction to peanuts. For two weeks, they're going to take a capsule that contains 1-200th of a peanut. That goes according to plan. They will increase that by 25% for another couple of weeks.
A month into this thing, they're still basically taking 1-200th of a peanut. But you will continue to do that. They will not hit the threshold of a full peanut by the end of the year. They're really, really microdosing this in the true sense of the word.
Well, you're super smart because you do the math. But in general, we've worked it out. Thanks. Goodness to the science where we know the steps. There are going to be certain steps of this where you don't have to increase by 25%. So once you get up to about 40 to 60 milligrams and that's only after a couple of weeks, we start to go up those steps. You start to skip and then you can go even higher. Even go steeper. Then we double, we can call Drupal. So that by the end of the year, you are at about a peanut to two peanuts worth.
That was done with science. There were dose finding studies. There were maintenance finding studies and we do this for milk and egg and tree nuts and peanuts all at the same time. That's the other thing because I told you a lot of people have more than one allergy. We had to work this out scientifically to go low and slow, but within reason so that we could eventually within a year and make sure that that flip was happening in the immune system and make sure that by the end of the year,
If they didn't want to continue anymore, we at least needed to get them up to an accidental ingestion of that food. So we were very careful to design this, and that's in essence why this needs to be a drug, because all that science, you can't do this at home, all that science enables you to know, when do I push the immune system to go quadruple? When do I not?
And what are you using? Are you looking at the IgG level? Are you simply doing this based on the absence of symptoms in the presence of the administration? Thanks to a lot of pioneers who were in those trials, including our patient, we were taking blood every two months, every three months. We were using blood biomarkers to let us know, oh, look at that. The cell immune system has started to switch. Oh, look at that. Isn't that interesting? The humeral immune system has switched.
So that's how we knew to change our protocol. That's how we knew it shouldn't take 10 years to do this because there was this natural switching that was happening underneath in the blood. So we use those markers to then readjust and recreate our regimen so that you could go low and slow in the beginning.
Then by about three months, we knew that the muscles were starting to change, so we could hike up the dose a little bit more by six months, even more. By year, we knew we had it because by that time, the immune system had switched, but that took a lot of time and effort and blood draws from those original pioneer patients to give us the science by which we could perfect this regimen. It's not perfect yet, but it's much better than where we were 10 years ago.
If at the end of a year, you kind of alluded to this, a patient says, look, I can't handle coming in here every day to do this anymore. I'm sort of done with this. Is it on average safe to assume that they may never be able to just go out willy-nilly and eat nuts, but if they accidentally ingest a nut here and there, or there's dust from a nut in a food and referred to as an accidental ingestion that they're going to be fine? Is that directionally trying?
You're absolutely right. On one side, we want to make sure that we reach the goals of the patient. Typically, a patient wants to get up to accidental level ingestion. And because of that, we say, OK, we'll try to get you up to 600 milligrams by the end of the time.
We also know that 600 milligrams is what the FDA also thinks is the appropriate threshold. So we're grateful for that knowledge across many other communities and institutions. So we try to get it up to 600. But you're right. Oftentimes people say, well, I'm done. I really don't want to have to do this every day. Can you please tell me if I could take my dose weekly or if I can take it every other day? And what dose is safe enough?
For maintenance, for example, we try to get them up to two peanuts a day. But sometimes they go off to college. They don't want to have to take a nut every day. But we tell them that you kind of have to because we don't know what will happen if you stop.
And that's what we told them five years ago. Now we have some long-term follow-up. Now across many countries, people are sharing data and saying, what makes sense for patients? Can you predict who can stop therapy and who might not be able to stop therapy? Who can go down on their dose during long-term follow-up and who might not be able to go down on their dose? So we're learning, but in general, it's much better to take about one nut or two nuts a day
every day after you've finished your therapy with a doctor. And just to be clear, do they ever transition to the point where they can do this as outpatients on their own, or do they always have to do this in a doctor's office?
After about a year, even after six months, if people get up to that one to two peanuts a day or hazelnuts or glasses of milk, you can say, all right, you're done now and you can go home and do this at home and then let me know how you're doing. So yes, after you get to that threshold, we definitely let you go home. And that depends on the clinical trial though, but nowadays in the clinic, that's what we do. Are people undergoing this therapy outside of clinical trials yet?
They are, Peter, and that's been going on for a while. We were very careful to say that if you do decide to do it in an outside clinic, try to get your health insurance to approve. We want to democratize this. We don't want it to be only available to certain populations because everyone gets food allergy and sees no boundaries in terms of ethnicities or socioeconomic status. Especially people of color have a much higher rate of anaphylaxing, unfortunately, because of access to healthcare. So that's a whole nother topic for social determinants of health.
But yes, there are clinics that are offering this and there are clinics, for example, latitude in New York City and San Francisco now that offer specific regimens that are based on science and evidence to be able to offer therapy. So there are unique clinics out there that are specializing in food allergy care to be able to help patients based on scientific methods.
What fraction of patients who continue this protocol get to the point where they completely shed the allergy altogether and at some point will go on to eat as many peanuts as they want.
I always like to start any conversation with a patient that this is possible. Some patients just want to be able to eat one to two peanuts for the rest of their life and just know that they're not going to have an actual ingestion, they're willing to do that. And they believe that is the word cure. But for me as a doctor, I kind of push my own standard a little bit higher. Like, cure should be eating on live and not having to worry at all.
So in that definition of cure, if you take the dose for at least two years, you have a 20% chance of being in the cure category, 20% after stopping after two years. After five years, you have a 60% chance. So time on dose matters as well. And again, it's all recalibrating, re-educating the immune system.
And many people ask me, well, are there some people that are refractory? And you'll know that term because of people that are refractory to cancer therapy. But in allergy, there's no refractoriness per se. If sometimes people have too much abdominal pain or they have too many hives,
or their asthma gets worse every time they have the dose, that's where I'll say, hey, it might not be worth it. There's too many side effects here. This bothers you too much. We try to decrease the dose so that we personalize it for them. But some people just say, this is too much now. I really don't want to go through it. So those people will stop doing it. But in general, if you stay with it, you'll get the benefit from it.
What percentage, if any, of people going through the clinical trials required epinephrine during the administration of immunotherapy? Nowadays, because we go so low and slow, it's a very rare percent. So about 1 in 10,000, and some clinical trials 1 in 100,000. It's rare.
Is there any allergen that is not amenable to this type of therapy? As you said, you mentioned a few others, shrimp, other fish, non-shell fish. Is there anything that we've uncovered which this therapy does not work?
It's again, back to that very elemental nature of the immune system. Proteins, any protein you can do this with, which is great. Very carefully, if you're allergic to a protein, which is what we're talking about today, you can do this. There are very rare allergies where you're allergic to a sugar. It's called alpha-gal. And we don't think you can do this type of regimen with alpha-gal allergies, because that's a sugar.
So with proteins, the immune system has this very elemental way of readjusting and recalibrating and become tolerant. But with sugars, it's a little different, but luckily sugar mediated food allergy, it's one of a kind, it's called alpha-gal, and it's very rare. But it is occurring more in the southeastern part of the United States because it's associated with a tick bite. So that's another whole area maybe in the future, Peter, for you to look at. But right now,
There is nothing that we have not been able to desensitize a patient too with food allergies that we've tried to.
Going back to sort of the environmental allergies here in Austin, we have this thing called cedar fever, right? So the cedar trees give off a ton of pollen and knock on wood. Unfortunately, it hasn't afflicted me, but I know so many people here who for a period of, gosh, I think it's sort of December, January or November, December, January, where they can't function without Benadryl and Zertek.
I've asked around on behalf of friends to see if there are immunologists and allergists here that have an immunotherapy regimen. And to my surprise, nobody does. Would this be an easy thing to address? Cedar allergies are interesting because the cedar protein itself is something called a protease sometimes. So it can start to grade proteins. It's a little weird, but cedar allergies are very serious. And yes, there are people that have developed immunotherapy for cedar.
It's interesting that I can't find them in Austin. I'll have to connect with you offline for this. There are a lot of people here who I know would be interested in that.
Yeah, it's the same rubric. You can desensitize to it. Although it takes a lot of care, maybe that's why importantly, cedar allergies are something just like other tree allergies. They're really to be cared for and they can give you lots of mucus and asthma. So I hope that those individuals you take care of can get some benefit, but immunotherapy. So I call it proactive therapy and reactive therapy. Reactive therapy are all those antihistamines people need to take proactive therapy is the immunotherapy to readjust your immune system.
I want to now talk a little bit about air pollution just for a moment. Tell folks what's a PM 2.5 and why should somebody care?
Ten years ago, I didn't really understand all of the PM2.5 jargon either. So I want to just make sure in all humility, this is something that we all need to learn now. Every single one of us, even if we're in a research station in Antarctica, because air pollution, unfortunately, is rising. We need to know that there are no boundaries when wildfire smoke happens in Australia. It can circumnavigate the world within four days.
And PM2.5 is a way that we as a society have given a measure to air pollution. But it's not everything in air pollution. It's particulate matter. It's the particles in air pollution that are 2.5 microns in size. Now you think, well, what in heaven's name is that? Like 2.5 microns. What does that mean to me?
Well, if you think of like a little red blood cell, that's a micron. So you think about particles that are basically about twice the size of a red blood cell. And those are floating around in the air. And why do they do that? Well, that's because partially combusted fuel, combusted fuel from our cars. If you don't have an electric car, combusted fuel from industry, when it breaks up petroleum, when it breaks up
Any kind of product would fire as well. Little particles escape into the air and those particles are not what you see as soot on your car. They are not what you see as brown dust on your house. These are particles that are so small they continue to be aerated and they can float in the air around the whole world.
And they're so small that they can penetrate into our lungs. And why do we care about that size 2.5 microns? That's because it can get through our lungs and into our blood. It's dangerous also because PM2.5 as a defined
measure of air pollution has about 200 different chemicals in it, 200. And of those 200, some of those are what we call volatile organic compounds. These are compounds that you smell when you smell like markers, like xylene, or in the old days, mothballs, naphthalene. So these are chemicals that are not good for the body. They are from combusting fuel.
If any one of your listeners is a chemist, these are what we typically call six-membered rings. They're organic chemists, sort of nightmares because they smell horrible. And I didn't like them when I was doing organic chemistry when I was a student. I don't like them now because now I know what they can really do to your body. They can cause cancer. They can increase asthma. They can increase cardiovascular disease, stroke.
And wildfire smoke is even more potent as an air pollutant than PM 2.5. We also measure PM 2.5 for wildfire smoke because wildfire smoke basically is biomass burning, but unfortunately wildfires aren't burning just
trees anymore. They're also burning commercial buildings. So what goes up in wildfire smoke, compared to, let's say, just diesel from the car, which is bad enough. But in addition, with wildfires, you're burning up your upholstery, you're burning up your paint thinners, you're burning up your detergents underneath your sink, your shampoos, that's all going up in the air. And that's also measured as PM2.5 because all those particles are so small, they're also going into your lungs.
So, with wildfire smoke, we also have to be super careful. So, for any person that's getting exposed to any PM 2.5, you can look on websites. You can go look at air now. You can go look at the NOAA website and know in your region what air quality index you have that day. If it's in the green zone, great. If it's in the yellow zone.
please start wearing a mask, basically a mask that you used to wear in COVID, because those masks are very important to reduce the risks of those exposures to your lungs, especially for children and elderly patients. So that's what PM 2.5 means. And I want people to really understand that it's measurable.
It means something biologically that's important. It means something medically, but it also can be measured by well-meaning agencies like the EPA, like we use in California, something called Purple Air, and you can actually look on the web. The Purple Air monitors can actually tell you what PM 2.5 measurements are in the air. Not all countries have that. We're lucky in the U.S.
that our US agencies measure PM2.5 on a regular basis so that we can map that to our zip codes.
Do you recommend that people, because there's a lot of PM2.5 monitors that you can buy for your own home, is it necessary or do you feel that if you are just looking at these databases, you get a good enough sense? Because I can't tell which problem they're solving for. Are they basically trying to say, you need to make sure you don't have particulate matter in your home, because if you do, by the way, it might be that you have a leaking stove, or I mean, that would probably turn up as carbon monoxide or something else, versus no, you just need to know,
what the level is outdoors because that might be the day you choose not to do your 10 mile run if it's a red day. All those things. So first of all, if you know that you have to be outdoors and you're an immigrant farm worker and you have to be out there for eight hours, no matter what, and the air quality index is 100, like it was yesterday here in California and we had people out in the fields, they should know that they should wear an N95 mask.
And N95 will sufficiently prevent PM2.5s from getting in. Not perfectly, but at least it reduces the risk. No mask completely reduces those small organic molecules, those six member drinks from getting through the mask, but at least it's better than nothing. So typically that's what I'll say.
And I'll definitely say to my patients, please don't exercise during any air quality index that's greater than, let's say, 50. Because even though they might not feel it during the hour that they exercise outside, it definitely affects their immune system. There were studies done in London, for example, where people would exercise out in the streets that had a certain air quality index. And in London, you can actually do this because there's micro
PM 2.5 measurements in Hyde Park versus in Broad Street. So they did this research and they knew that even if people exercise out for one hour and clean air versus polluted air, their immune system changed for a whole day based on that one hour of exercise. Be careful. And yes, indoor air is very important. Our lives are spent
indoors for more than 90% of them. That means 90% of the time that we're on this planet, we're spending it indoors. That's typical for the average US citizen. So having a Purple Air Manager indoors is actually helpful, especially if you live in a place with lots of wildfire smoke or air pollution, because you can't assume
that your air pollution is being filtered appropriately and you can't assume that you're being protected because oftentimes you can't smell this and you can't see it. It is so small that you need a special detection monitor to know if it's there. Now, if you do have bad indoor air, you can buy a MIRV
filter. You can buy a filter in your air conditioning or central air or you buy a stand-up filter to reduce the exposure. So all these things are available to people and in certain states they are available freely for families that can't afford them.
So just to be clear, let's say you do this exercise, you buy the purple filters, you figure out that, hey, actually, either AI live in an area where there's enough pollution outdoors, and of course it's easily able to get indoors through windows and doors. Or just for whatever reason, there's something in the house that's producing these compounds. Option one is you just get stand-up HEPA filters for the house, but you're saying option two is there are certain filters you can put in your HVAC that will do the same thing. And what are those called again?
They're called MERV. They're MERV 13 or higher. Don't buy a MERV 7 or 8. MERV 13 reduces all of the major PM2.5, as well as polyins, as well as other chemicals, but you need to change them often because they're getting clogged up. I don't work for purple air, but you can buy any of these monitors that can monitor external outside air and indoor air, and you can buy them and get to know the difference.
It's good to ventilate your home so you don't want your home to also, like you said, be collecting its own toxins and that can happen if you have a gas stove or a wood stove. So yes, in general, knowing and measuring your PM2.5 is going to be helpful to your health because you can manage accordingly.
Do you have a sense because I've never been able to get a great answer to this question, Kerry, it's actually one of the reasons I did not include this in my book. I wanted to include a section on air pollution in the book. And in the end, I didn't for a couple of reasons, but biggest reason was I couldn't get a really clear sense of the mortality impact.
I couldn't quantify it the way I could quantify it for smoking, obesity, and some of these other things. So coupled with the fact that the book was already about 50% longer than anybody wanted it to be, do you have a sense of the magnitude of this? And for example, like, what's the difference between even quantifying the exposure is a little difficult. It's not like pack years of cigarettes where we can say 40 pack year history versus zero pack year history translates to this much difference in outcome.
Yeah, actually now, Peter, you can. So the WHO just put a report out, the AQLI just put a report out from University of Chicago. I'll send it to you. I want to make sure you have this because you have such a wide, amazing opportunity to influence people through your bandwidth. And Peter, I feel like you are in this incredible position to make this impact with others. You are a trusted voice.
And because of that comes the privilege of being a trusted voice, but also that accountability and responsibility of knowing all the science. And so what I'll do is send you this report because it has now been put into exactly those terms. And it's more dangerous than tobacco smoke because it is so prolific. And I'll give you this report because in the first page, it shares with you the context of how pollution has killed about eight to 10 million people a year now.
And that's attributed directly to air pollution. What is the final common pathway? Is it majority through cardiovascular disease, cancer? Where do we think the actual mortality comes from?
Exactly. Especially in low to middle income countries, it's cardiovascular disease and lung disease. In quote unquote, more westernized countries, it's more associated with stroke, long term cardiovascular disease and cancer. So I'll send you this. I think it's important for you to know.
Air pollution has now, thanks to a lot of science, that you can disaggregate what deaths are due to air pollution versus what deaths are due to tobacco smoke. There's a multiplicity of effect here, but now the epidemiologists really have the data right, and you can sink your teeth into this data and know that it's accurate.
Well, Carrie, this is very interesting. I know we were a little bit short on time today, so I'll kind of just ask you one final question. When you go back to that child who died in the ICU, the child who was kind of your patient zero, you alluded to it, but we never really got to it. Tell me, why did the EpiPen not work? When that father asked you about that, what happened there?
They hadn't renewed the EpiPen. It had expired. They hadn't gone to the doctor for at least five years. And they assumed that their child had grown out of a milk allergy because that's what people told them would happen. But they never got their IGE retested. They never went back to their allergist. And so they still had the EpiPen that had been given to them five years prior and it had expired. In addition, it was for a different weight. It was for Epi Jr.
and he had gained and, of course, grown. So if he were to even get an epi that was not expired, he should have gotten a different dose. So it interlaid all these aspects about the fact that you cannot know just what typically happens to a patient if that happens to you. You need to actually go to a doctor and get your own set of data to figure out how to best manage your disease. It also
taught the lesson of you've got to keep updating your EpiPen and making sure that it's renewed and not using an expired chemical or any expired drug. And then lastly that as you grow you need a different dose.
Wasn't there a big controversy a couple of years ago when a company that was selling EpiPens decided egregiously for no apparent reason other than just malicious greed to jack the prices up? Has that resolved and are EpiPens now relatively inexpensive again?
That's right. That company was my land and they were making epic pens. And that's why I called it an injectable epidephrine device because now there's a lot of them. Thank goodness the FDA, other agencies got involved and said, okay, this is not right. You cannot keep charging that enormous amount of money.
And so then what we call generic epinephrine devices started to be made. Other companies started to hit the road. There's other devices now that can be used called the Avocue. So I think luckily now, thanks to many industries involved in this, there's also potentially a nasal epi that can be used. So yes.
That company was seen as providing methods that were not ideal at all, and that was stopped, thank goodness, because no one should be charged that amount of money for a life-saving drug. What were they charging for EpiPens? Oh, it was like 400 up to 600 for some of my patients. That luckily now is being covered by insurance, but again, third-party payers also need to make sure that they can reimburse for these life-saving medications.
Well, Kerry, this is really interesting stuff. Look, I've learned a lot today, certainly getting the differences in some of the immunology here. Also, I think the PM 2.5 story is something that I look forward to digging into a little bit more, especially as someone who does spend a lot of time outside, maybe no more than 10% of the time like anybody else, but it seems like I spend more time outside. So I'd certainly like to be aware of that.
Anyway, thank you very much for most of all your work. I've seen firsthand the impact it has had on people's lives. And I know that there are probably a lot of people who are hearing about this for the very first time today. There are people who are listening to us or watching us who know somebody who suffers from a devastating anaphylactic reaction, who probably at this point in time are completely unaware that such a therapy exists. I guess my final point is, what would you suggest for those people? Someone listening or hearing this who is being blown away by what you're telling them?
Where can they either find a clinical trial or find a non-clinical trial provider who's able to walk them down this pathway? Well, first of all, thank you, Peter. Thank you very excellent questions as always. I'm really excited to be on the show and thank you for your curiosity and your care and this podcast. For people that are learning about this new week, what's wonderful is you can get on your computer, do a search on clinicaltrials.gov.
look under the category of food allergy, and you can find out what clinical trial nearby you is actually ongoing for food allergy therapy. And there's a lot more than there were just five years ago, so that's good. There's like 17 companies in the space now. I'm really excited about the future. There is a lot of hope and promise. Within that hope and promise, there are more clinics around the country as well that are specializing in food allergy. I gave you one example of latitude, but there are others as well.
And so with that in mind, I would go to your healthcare provider, ask them questions. If you feel like they don't have time or they haven't really answered the questions in the way that you learned about today, go online and find out those clinics that specialize in food allergy therapy. And again, not everyone fits with everyone, so give it a test, see if you like that structure, and then you can try. And I hope the best because that possibility is there, that reality is there, and I hope everyone tries to undergo therapy.
Kerry, thank you so much. This was absolutely fascinating. Thank you. Thanks for your great questions. Thank you for listening to this week's episode of The Drive. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members. And in return, we offer exclusive member-only content and benefits above and beyond what is available for free.
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