Narrator:

Introducing Doctor Benjamin Gold, a highly regarded pediatric gastroenterologist. Prior to joining Children's Center for Digestive Health Care, LLC in 2009, he held esteemed positions at Emory University School of Medicine, including the Marcus Chair of Pediatric Gastroenterology. With over 175 peer reviewed manuscripts, 45 book chapters, and numerous educational materials to his name, Doctor Gold is internationally recognized for his expertise in pediatric esophageal diseases.

Helicobacter pylori infection, and gut microbial interactions. He founded the Arrow Digestive Center and Program at Children's Health Care of Atlanta in 2005, and has served NASPGHAN in various leadership roles, including as immediate past president. Please welcome Doctor Gold.

Doctor Benjamin Gold:

Good morning. Bienvenidos and welcome. I have the indubitable pleasure of being your lead off today. No, I am not. Siobhan O'Mahony. She will come at the end of this, but hopefully you'll see during the three lectures that we're about to give that you're going to get a spectrum, sort of what Javier gave yesterday. So we go from the infants to the elderly, or we go from diapers to depends or gums to dentures.

And this way, since Siobhan is going last, it's sort of like Benjamin Button will go in reverse. So we'll go with the old guy first, and then we'll, have her as, the finish of this, session. First and foremost, I want to thank, the sponsors, for the opportunity, actually, and blessing to be here to talk to you all today. And thank you all for your kind attention, the multiple questions. Yesterday, we didn't get through all of those. And hopefully we'll have some time today. And then one of the things that we hope to do is at the end of all of this is to provide you with some practical tips, some practical points for you guys to bring back to your, practices and use in your everyday when you see patients, in your office.

So my job today is to really talk about how potentially we can alter what we call the allergic march. These are my disclosures. And as you can see, none of them had anything to do with respect to the specific content of this presentation. My objectives this morning are as follows three main ones. And again, I hope that in addition to the evidence in the science that I'm going to give to you, that there will actually be some practical take home points that you can use in your office. Because in the end of the day, it's not just modifying a disease that exists. It's hopefully preventing that disease from occurring in the first place. So I'm going to talk a little bit more on how cow’s milk protein and the allergic march, which you've heard about already progresses over time. And in essence, how do you achieve a timely diagnosis with a child, that or infant that's already having symptoms?

And then mitigate or mediate against those, those symptoms, and hopefully get that child as they get older to be able to tolerate the very food proteins that they have reactions to. I'll talk about the importance of early dietary intervention as Nitida said in the beginning in her introduction comments. At what you do now may affect something later on in life. And in fact, there are ways to alter disease courses that in fact, have good outcomes. And we'll talk about how to interrupt the allergic march by appropriate treatment of cow’s milk allergy. And finally, an area that I've been very involved with for most of my career is the relationship between the microbes in our gastrointestinal tract, and the, gut mucosa and more importantly, the immune system and how it affects disease.

And our immune development over life, and in particular, how we can influence the microbiome for healthy outcomes. It's important to recognize and put this in context of what we see today. I mean, we're a society. And I'm going to keep my eyes on you that, you know, people are always doing this and looking at their phones.

They're scrolling through one page after another. And you can see that whether it's, during the pandemic, pandemic inspired food labeling raises alarms for people with food allergies. To more recently, food allergies, is a body's bad immune reaction to a certain food. And importantly, understanding that maybe since we all don't live on farms and roll and play in the dirt when we're infants, that actually our pets that we have at home might actually be a good source of enrichment of our microbiome.

I always ask my patients when they come into the office if they have any pets, and then if they have pets. I asked them what the names of their pets are and usually get the parents to look at me. Why does he want to know the name of my dog or my cat? And I said, well, what happens when you come into the house? Who's licking who? And so that's the expression, if you will, of the microbiome and sharing of it. And there's actually elegant science that looks at how a pet in the household may be supplanting, the lives we used to live when we were living in rural environments and rolling in the dirt.

And in particular a more recent thing and actually, this is very fitting, given, Professor Rich's, talk at the very end of this program, the fact that, social media and I don't know how many of you all, have patients that come into the office, and they're telling you what they learned on Doctor Google, Nurse Wikipedia or medical TikTok because they already have diagnosed their child or their infant and they're telling you what to do instead of asking for your advice. And this recent paper in the Annals of Allergy, Asthma and Immunology, 93% of this large cohort of parents had done some type of internet searching prior to going to see the doctor or the specialist for the first time.

Now, why is this a problem and why are we talking about this to you all today? As a card-carrying epidemiologist, I have appointment at the CDC and foodborne and Diarrheal Diseases branch. So I like to think about problems that I see in the office as it affects populations and populations that are not just in the metropolitan Atlanta area, but worldwide, because it's important for us to understand diseases as it affects populations in order to impact on those, particularly those that have a problem with public health.

You can see here, the y axis, is percent. The x axis are year cohorts and you can see that allergies have been increasing dramatically, whether it's food, skin or respiratory and in particular, skin allergy, atopic dermatitis or eczema has increased over 70% over the last, 20, 25 years. The nine most common things that you need to think about in your office and it's important yesterday, doctor Lightdale alluded to the fact that there may be two different types of pathways that allergies occur. One is where all the tests are based on. That's IgE-mediated allergy. And there's also non-IgE-mediated allergy. But the nine most common IgE-mediated allergies are allergens are shown here nine food proteins 10-15 years ago this was six.

So it's clear that we're developing more food proteins that we have allergies to. And it's important to recognize that milk or dairy proteins, casein and whey are the one of the most important that we have to worry about in infancy, and childhood and even in adults. And you can see here in a paper that was published, a few years ago, the food allergy epidemic, 33 million, at least this is in context.

The U.S. have allergies and importantly, 377% of claims, increase in terms of allergies from 2007 through 2016. And this recent paper has just published a couple of months ago, which is a beautiful study being done in Australia, a cohort of over 5000 one year old infants that have been followed, long term, very similar to the birth cohort that, doctor Lightdale described in her presentation.

And you can see here allergic diseases, 40% of primary school aged children with a third having multiple. It's not just one food that they were allergic to. And that challenge confirmed food allergy prevalence, that being the gold standard, if you will, was high and 45% had persistent disease out to about ten years.

Demonstrating that this is not something that is outgrown. And so we need to be thinking about those infants that we see in our office that have severe atopic dermatitis, that have bloody mucusy stools, and how to effectively, stop that and potentially, give rise to this concept, which you're going to hear multiple times, today that of tolerance and allow them to have the food proteins that they're allergic to.

Now don't get overwhelmed by this schematic, but I want to break down how our bodies react to food and environmental proteins, because I don't think we underestimate how much environmental allergens the ones that we breathe also impact upon, allergy manifestations. But if you start with here over on the right, milk allergens and then your intestinal epithelium, these APC which is antigen presenting cells, these are sort of these pluripotent cells just in the mucosa that then can differentiate into two major pathways.

One is the IgE-mediated pathway. And whether you realize this or not, all of the diagnostic tests that we have, the immuno cap, the Rast tests that you can do off the blood, the skin prick testing that the allergist does in their office, or patch testing, those are all based on IgE- mediated allergies, non-IgE-mediated allergy.

The things that Doctor Lightdale and I and Gastroenterology have to worry about. There are no diagnostic tests. It's really good suspicion history and physical exam which you all do in their office. And then figuring out which foods that they're allergic to. So you can see after differentiation to Th2 cells, eosinophils is a huge mediator. And then histamine release and the allergy manifestations. Non-IgE-mediated allergy, which is more of an inflammatory an autoimmune type of process, goes via a Th1 mediated pathway.

Interferon gamma is the signal and activated macrophages that give rise to mediated allergy one of the hottest areas if you will in immunology I think and an area that potentially can be, mitigated against and in which lots of, the new biologic compounds that we're seeing for things like, eczema, asthma and eosinophilic esophagitis are these, traffic cops, if you will, in the immune system called T-regulatory cells. And they can drive the pathway one way or another. And I'm going to talk about how you can potentially intervene, with what you do. Now remember I talked about Doctor Lightdale, l alluded to the fact that there's two major pathways by which, and there's a really a third, which is mix, but there's non-IgE-mediated, triggered by other components of the immune system.

It's typically a delayed presentation. And from a gastroenterologist perspective and actually these are the ones that show up in your office in the general pediatrician's office first presenting usually with GI symptoms, vomiting, bloating or diarrhea. IgE-mediated triggered by the immune system producing IgE antibodies. Symptoms usually are quick and onset, and these are the ones with the very severe allergies that that children are carrying. The EpiPen that they can use to stop that specific reaction. And then there's some people that have mixed IgE-mediated allergy. For sake of time, I'm not going to talk about this entity that has now come about called FPIES food protein induced enterocolitis syndrome. But that's actually the non-IgE equivalent of the anaphylaxis. So the child that is very allergic to peanuts develops hives, then starts wheezing. And then has, you know, the asthma attack and needs either the EpiPen or go to the emergency room. FPIES is profuse vomiting and or diarrhea that occurs literally within hours and sometimes a day of the ingestion. And it used to be just affecting infants. And we now know that it can affect young children, adolescents. And there was two recent papers that it can even affect adults. So this is these are things that we all need to think about. And allergies tend to run in families. So it's very important that when you're seeing an infant or child in your office that has the symptoms that worry, that makes you worry about allergies, that you ask a family history.

Now, there are a number of foods that have been involved in Non-IgE-mediated allergy. And these are different then IgE-mediated allergies. And they're shown here unlike in IgE-mediated allergies where there's less than a 20% cross-reactivity with soy. Soy still is a good substitute if you have IgE-mediated allergies. Not so for non-IgE where there's more than a 40 to 60% cross-reactivity between dairy and soy proteins. In addition, when you start introducing, you heard Doctor Rodriguez's lecture yesterday about complementary foods and you start introducing cereals, rice and oats in non-IgE-mediated. allergies actually confer a higher rate of both cross-reactivity and allergic response. And we're even seeing things like fish and fruits, food proteins that we really never used to see in children that have non-IgE-mediated allergy.

Now this somewhat busy schematic is to break down some of the things that you're going to hear much more eloquently done by Patrick in his talk elsewhere, which is the difference between what's good which is tolerance and what's not so good, which is allergy. What's important to recognize is that intolerance, early exposure. You heard this a number of times yesterday.

And how we now believe that, introducing foods early on in life, not the six months or later, can actually, induce an important immune response called tolerance, versus at later in life if you leave them out, and so early introduction allergy, early allergen exposures, a rich microflora that's very diverse gives tolerance, environmental exposure. You do not have early food exposure. And you have other things like antibiotics. That gives rise to allergy. The take home point is that when you think about the microflora, the microbes that line the gastrointestinal tract in children with allergy, they have the concept I want you to take home is dysbiosis. They have a very non diverse microbiome.

Diversity is good in the microbiome. And children with tolerance have a diverse microbiota. Now what are some of the manifestations. A GI talk would be deficient if I didn't show you endoscopic pictures. I promise there are no poop pictures. Well, maybe one at the bottom. But I won't show any vomiting pictures. Not very good for you all to see right after breakfast. So one of the things that we're starting to see more and more again is this entity called eosinophilic esophagitis. Abbreviated EOE in North America between, a recent paper published just last year in the Annals of Emergency Medicine. It is the number one cause of 11- to 17-year-olds showing up in emergency room with food impaction.

And so we're seeing this all the time, and I can't tell you how many relatives of patients that I see, uncle Bob, who constantly gets up from the table, who needs to drink lots of water or goes to the bathroom and is choking and coughing and then comes back down and maybe even has seen an adult gastroenterologist, but never got any biopsies, so they didn't know that they had EOE. Small intestine disease. Although celiac disease is not necessarily a food allergy, it's mediated by a Th1 or non-IgE pathway. And in fact there's lots of data that show that early introduction of gluten, even in high risk families for celiac disease can prevent the development of celiac disease. And there's lots of exciting research in this area, allergic colitis involving the colon. And one of the more common things that you'll see in the general pediatrician's office are children that come in with blood and mucus in the stools, who have cow's milk associated allergy. And just so that, you know, not all of these are endoscopic pictures, this was taken through anoscope, on the rectum of a little infant that had bloody mucasey stools, bad eczema.

So you can even, in the pediatrician office, diagnose. These are, punctured hemorrhages, that give rise to the display. Mucasey stool. And so cow’s milk, protein allergy. Now, why is this important? And why do I have to worry about this now and then later on? And it's important to recognize in this sort of simplistic slide, the y axis is incidence. For those of you who forget their epidemiology prevalence, if I asked you all in here to raise your hands if you had an allergy to one food or another and every, there were a bunch of people that raise your hands. And then we came back a year later and I asked the same question. The one who raised their hands here.

Now, that's prevalence. It's the frequency of a condition. At one point in time incidence. You follow that same cohort over time, and you look for new cases. Incidence studies are much harder to do. But you can see incidence. So new cases of eczema food allergy asthma and rhinitis. And this is years in high rates of a skin allergy early on. But you can see they start developing ears, nose and throat allergy. Respiratory allergy. And these change over time. So the concept of the atopic mark is, is that it's an association between, IgE-mediated allergy, early and then allergy manifestations later on in life, 2 to 4 times the rate of eczema later on in life, 3.6 times respiratory allergies and four times the increase in, asthma. And this risk is increased when there's, multiple food allergies. And how do we, mediate against that? So there are a number of strategies and you're going to hear about those, during the lectures today. And it's important to recognize that there are ways, and you heard some of this yesterday to mediate against this. Now, why is it important to introduce foods early? And Doctor Rodriguez, alluded to this, as did Doctor Lightdale. The study was called the sleep study learning early about peanut allergy. And actually it shows how observation is important. The people who originally started this were looking at two different population of Ashkenazi Jews in Israel and in New York. So genetically very, very similar. And they noticed that in Israel they gave a peanut containing substance very early in life, whereas in New York they weren't giving it till six months, eight months, ten months or a year. And they also noticed that there were much, much higher prevalence of allergies in the New York population than in the Israel population.

And so they said, maybe there's something about early introduction of peanut products that mitigates against the allergies. And so the lead study came about and what they showed in a very compelling way, whether they had non-league or IgE-mediated allergy, was that early feeding of peanuts, arrested the likelihood of developing allergies later on in life. And so the American Academy of Pediatrics had actually changed their recommendations.

And in 2019, no evidence of delaying introduction of allergenic foods, milk, eggs, tree nuts and fish between 4 to 6 months of age, peanuts between 4 to 6 months of age, particularly in families where infants are at high risk for allergy. A very practical, important point for you to take home. And you can see here in, a, LEAP trio study. So this is a follow of study that just got published, this past June. So a month ago, they showed that, in fact, in this, to, study, a number of infants that again, if you continue with early introduction and follow these babies over time that even by the time they reach early childhood or, early adolescence, they still have, no evidence of allergies. Now, how can we change this? And the last few slides are going to focus on how we can actually mitigate this, allergic march, either in those who come in with symptoms of allergy or those who don't. First is, how do you change the protein that they're getting into dairy protein, whether it's casein or whey is shown schematically here.

And if you break the protein down, either take one protein out and partially hydrolyze it. That's shown here. Or extensively hydrolyzed the protein into smaller pieces called extensive hydrolysis, or even take it down to its basic building blocks of amino acid base. These are your therapeutic formulas. You can actually change both the active disease. If you have an infant that has active cow’s milk associated allergy, and particularly those infants that are fed extensively hydrolyzed proteins, you can actually develop tolerance to that specific offending allergen so that they can tolerate it later on in life. So extensively hydrolyzed formula, which is devoid of the large three-dimensional shape proteins that our body's immune system reacts subversively to, can actually benefit by developing tolerance later. Amino acid based formulas. And that's important for you to recognize when we see children that are so severe that they have to have amino acid based formulas, but in fact, these don't impact on tolerance.

And so you have to think of ways to strategically start reintroducing, even going back to an extensively hydrolyzed formula to induct, induce tolerance. And you've seen this slide multiple times. And I'm not going to take away, doctor O'Mahony’s Thunder. But I actually have a slide knowing that she was going to be talking this morning, that I'm going to show you in a minute, but the important thousand days I'd like to venture to say actually can be a lifetime.

So it's not just a thousand days, which influences our microbiome. And one other concept for you to take home. Microbiome is two components. The microbiota, which are the microbes that are there and their byproducts. And that makes up the, the whole microbiome. And this important study, a longitudinal study that demonstrated that, in fact, you can actually, modify risk, by increasing the richness or diversity of the microbial species through school age and even in teenagers. So the microbiota may have an opportunity to be intervened upon even later on in childhood or in adolescence. And if you think about the concept of before, delivery, so there's lots of discussion about, C-section as being all bad. Well, there's some babies that there's no way that they would be able to live if they weren't born by C-section.

My daughter, for example, was born at, 32 weeks, emergency C-section because of an abruption. And actually, she's fine. But, food allergy was an issue that we were very, very worried. These, elegant studies are published in Nature and Genetics, within the last two years, which actually demonstrate, bacterial species in the intestinal tract of, fetuses between 16 to 20 weeks gestation, foundation species, which in fact had one bacteria that was important in the inflammatory immune response. So M. luteus a reduced pro-inflammatory chemokines and induced, memory. And T cells so important very provocative data that says maybe even what mom can do during gestation. And Doctor Mahony, see, I'm setting up the softball for you. It's going to go on this in more detail in her talk in terms of what even, pregnant mothers can do to influence the microbiome of their not yet, delivered, child.

One other concept for you to take home is dybiosis. You've heard this mentioned multiple times, but it's never really been formal defined for you. Dysbiosis is a perturbation of normal microbiome. We were wanting to get to a diverse eubiosis, but in dysbiosis it was where it's disrupted and you have a decreased diversity and you get the result in other diseases and you name a condition within the gastrointestinal tract. And somebody is looking at the microbiome and its relationship to that disease. And in fact, you can see a number of different diseases. And I highlighted allergy down here where dysbiosis can result in the actual disease outcome, ranging from celiac disease to preterm infants, Necrotizing enterocolitis. A lot of really important work going on in obesity, in terms of looking at the microflora and metabolic syndrome and an allergy, decreased counts of good bacteria, Lactobacillus, bifidobacteria and a decreased overall diversity in the gastric microbiome. So in fact, we actually have every single part of our body has its own unique microbial signature. And in fact, as someone who used to wear contacts for many years until and I kept, you know, falling asleep with my contacts on so I get these wonderful things called corneal ulcers. And I thought it was very surprising when I got to my ophthalmologist after getting one of those, where he said, you know, that actually the microbiome on the cornea gets reduced its diversity when you wear contact lenses.

And in fact, they're actually coming up with, believe it or not, probiotic eyedrops, that you can enhance the microflora. Yes, probiotic eyedrops soon to be available in a store near you. But the take home point is that each of our body parts actually has its own microflora that interacts with the epithelium in the compartment of the body that they're involved with, and more importantly, the immune system to result in, disease. So we have this sort of super organism, if you will, the gut microflora, which can be bacteria, fungi, viruses, and even parasites and protozoa that make up, the microbiome. Now, what about this LGG? You heard about this somewhat yesterday. LGG is probably the oldest and the best studied of all the probiotics that are on the market.

Realize that I don't care where you go in the world, probiotics is an unregulated market, and there are lots of probiotics that you can buy commercially that I mean, say all kinds of claims. You can walk on water, part the Red sea, you can, you know, heal the sick. But in fact, there's really less than ten, that actually have data, good evidence.

LGG, actually has been reported to reduce the risk of atopic dermatitis, when administered to breastfeeding moms. So even if breastfeeding, you can augment the immune response, augments the microflora in the infant by giving probiotics and in preventing allergy developments in, when administered. And there's now at least a half a dozen studies that in the last trimester of pregnancy, giving probiotics to pregnant moms in at who have at risk infants of allergy, you may be able to change. And there's a number of anti-inflammatory or downregulation of pro-inflammatory chemokines. These are signals that the immune system uses to talk to each other that probiotics can mitigate against. And so you remember the schematic I showed you in the beginning? You can see here that LGG actually affects and helps the T regulatory cells. If you have a IgE-mediated allergy or drive it this way or if you have more of a non-IgE-mediated allergy, you can drive it towards tolerance.

So it's important to recognize that these probes actually have an important pathway, or part in the, inflammatory pathway. And what's the data show. So we use fecal cow protected in pediatric G.I. And you all can order this in your office because it's an objective of, a marker that you get in stool. It has a number and it corresponds to allergy or inflammatory disease or infectious disease.

So we can look at this. It's a neutrophil derived protein. And particularly if they have colonic or small bowel disease and it's elevated in infants who have bloody stools and calcium associated colitis. And you can see that if you use a formula. Now remember you're modifying the protein extensively hydrolyzed casein and you're adding a probiotic. And as is compared against those who were breastfed, those who had no LGG and then the orange are those that did have LGG.

This is enrollment. And then four weeks later you can see a dramatic reduction, in the fecal cow protecting. So an objective marker. In this study, 260 infants with cow’s milk associated colitis, five groups, extensively hydrolyzed casein alone, extensively hydrolyzed casein, plus the probiotic re-hydrolyzed rice formula, soy formula, and amino acid base formula.

And what they're looking at in this particular study is whether or not you resolve, the the disease and they can tolerate by a food challenge after 12 months, to see if they could tolerate cow’s milk protein. And you can see the yellow bars far, exceed the other formulas that, extensively hydrolyzed casein plus LGG builds tolerance in these infants with cow’s milk colitis.

And whether you compare IgE-mediated allergy to non-IgE-mediated allergy, you see the same thing. So the extensively hydrolyzed casein based formula plus the addition of the probiotics, dramatically enhances, the tolerance, the the ability of these infants to actually tolerate intact dairy protein, later on in life. Now, what does this a lasting effect. And the next few studies show you these and in particular you can see here. So this is extensively hydrolyzed casein. This is extensively hydrolyzed casein plus LGG. And then this looks at three year follow up. And they look for future. So this is incidence new cases of Atopy in these children in particular skin. And if you add the probiotic to the extensively hydrolyzed casein based formula you have a 50% or greater reduction in new cases or new incidences of Atopy. And this is shown here, similar type of, study, different authors. But again, allergic manifestations are reduced by over 50% if you add the probiotic to the ostensibly hydrolyzed casein formula. So you're changing the protein that they're getting, but you're still introducing it and you're changing and you're adding the probiotic to the specific formula.

And this shows the same sort of thing. 80% of children who had cow's milk associated colitis. So clinical signs or symptoms you're going to see in the office if given extensively hydrolyzed casein formula and LGG over 36 months they develop tolerance. And here a series of studies dating back to, over ten. Almost ten years ago. That and particularly focus on this one, a randomized, controlled, study of over 500 and for infants, and you can see that early and ongoing ingestion of cow's milk associated with a cow's milk protein, from 1 to 2 months of age was associated with significant reduction, by six at six months of age of cow's milk allergy.

So to summarize, and yes, I'm almost through his time. What I hope during the course of this presentation you've seen is that there are two types of allergy IgE and non-IgE. IgE-mediated allergies have quicker onset specific indications. And all the diagnostic testing that we do non-IgE delayed onset. And you really have to do a good clinical exam and get a good, history of that infant and the family.

Food allergies clearly are increasing worldwide. And there are a number of reasons for and that many of these that we see in infancy are precursors to the allergic march, if you will, to allergies later in life. And finally, extensively hydrolyzed casein based formula have a peptide profile that when added with a probiotic, can actually both, resolve the disease and help this immune response called tolerance for later on in life.

And what I like to leave you with is this you have the environment that affects our microbiota. You have the genetics of the individual infant that affects the gut microbiome. And we like to be in this you biotic or diverse happy microflora state which gives rise to health versus dysbiosis and allergic disease. And that if you can give probiotics and for sake of time. I didn't even go through prebiotics. You interrupt this dysbiosis and drive this pathway over here to eubiosis and health. And I think at that point I will close. Thank you so much for your kind attention. And I will turn it over to the next speaker.