Understanding FPIES: A Silent Food Allergy

Music. A fascinating talk. Let's listen in. It's my great pleasure to introduce this morning's grand round speaker, Dr.

Milin Pansari, who is a good friend of mine. He's an associate professor of pediatrics at Central Michigan University and Children's Hospital of Michigan. He did his pediatric residency at Henry Ford Hospital in Detroit and fellowship in allergy and immunology at Children's Hospital of Michigan. Subsequently, he served as the Associate Fellowship Program Director for Allergy Immunology Fellowship Program and also Medical Director for Asthma Program at Children's Hospital in Michigan.

His clinical interests include asthma, anaphylaxis, and food and drug allergies. His clinical research projects include improving asthma outcomes in inner-city children and anaphylaxis education in local schools, as well as improving access to rescue inhalers and epinephrine autoinjectors in inner-city schools.

At the national level, he's very active in numerous activities, including educational, scientific, and advocacy activities for the American Academy of Allergy, Asthma, Immunology, and the American College of Asthma, Allergy, and Immunology. Dr. Pansari, thank you very much for accepting our invitation. The floor is yours. Thank you, Dr. Kamath, for your kind introduction. First of all, good morning, everybody. And I'm wishing you a very happy Friday.

You know, today is a special Friday. Today is April 11th. And guess what? Today is the International Cheese Fondue Day. Do you know what it means? It means that we can go raid Cheese Factory, go to Mexican restaurants, American burger places, and eat cheese to our heart's content and enjoy. Isn't that a wonderful thing? But imagine a world, living in a world where even the most innocent food could trigger life-threatening reactions.

And there are really many patients out there who cannot eat these innocent food because they develop a serious and a severe reactions. This entity is not very uncommon.

We often would miss that if you have no knowledge about these entities. So today, my goal is to bring your attention to one of such clinical syndrome, which can potentially result in severe clinical reactions. Nope. I'm not talking about anaphylaxis. We know about anaphylaxis. I think we do a good job in taking care of patients with anaphylaxis. But I'm talking about a rarer entity.

Imagine patients living in a world having this disease syndrome, and we're living in a constant fear, anxiety, worried about when that next reaction could occur. I'm not making it up. It is real. This disease was not discovered until very recently. In 70s and 80s and 90s, many of these patients were not diagnosed appropriately. When they went to see a doctor, who would often give them an advice which was inconsistent with the clinical symptomatology.

Often they were told, I don't think food is responsible for this. I've never seen this problem in my life. And when asking for a specific advice, there was nothing to offer. So this patient lived in a continuous sense of despair and with a sense of abandonment. Certainly, this is a significant psychological impact when you have an uncommon clinical syndrome like this.

And today, my job is to bring your attention to this uncommon food-induced clinical syndrome. For many of you, this may be totally a new entity, but for a few of you, you might have seen this patient in your clinical practice. I certainly would like to know what was your clinical experience. And for presumably many who have not seen one as yet, my goal is to provide you a clinical update on this clinical syndrome. Let me illustrate this case. Let me illustrate this point by giving you a clinical

case scenario. A five-month-old infant was admitted to PICU following an acute illness. The infant presented with lethargy, sudden onset of severe emesis, and later, one large watery diarrhea. Infant was clinically well when dropped to the daycare in the morning. He also fed well on a Similac infant formula two hours prior. When he was brought to the ER, he's obviously a sick-looking infant, ash in color skin, lethargic, severe dehydration, hypertensive, and incidentally, was afebride.

His initial lab showed a significant neutrophilia, metabolic acidosis, methemoglobinemia. Otherwise, the pertinent clinical history was unremarkable. The child was a healthy infant, growing well, exclusively breastfed, was diagnosed with cow milk allergy due to his previous emphasis episodes. What was the clinical course? The child was admitted to PICU, treated for hypovolemic shock and possible sepsis. The sepsis workup came back normal, including a CSF in the normal range.

The infant made a dramatic recovery within 24 hours of presentation. So what's your likely diagnosis? Is it a case of acute gastroenteritis with severe dehydration? Unlikely because the clinical symptoms were very short-lasting and the patient made a very rapid recovery, did not have any fever, other signs of infection. Acute sepsis, yes, it was a very dramatic presentation, but again, equally dramatic recovery and with microbiological cultures being negative, again, was less likely diagnosis.

Is it a case of cow's milk anaphylaxis? Certainly not, because the presentation was at least two, three hours after his last feed, and he did not have any other system involvement. So typically, anaphylaxis would be a multi-system involvement, cutaneous, respiratory, GI, and so on and so forth, but he didn't have any of those. Is it a case of foot poisoning? Foot poisoning is quite uncommon in this particular age group, when a child was just infant fate formulas.

Again, the recovery, again, is quite dramatic. Usually, foot poisoning would not have such a dramatic presentation, then what is it?

F-Pi's. Yes, indeed. You've taken the meat out of my talk today. This child is a case of F-Pi's, a food protein enterocolitis. This child was not labeled so when he was discharged from the initial hospital. He later on was readmitted around 12 to 13 months of age to our institute. Again, with a very similar dramatic presentation, he was resuscitated by the EMS, actually intubated on site because of concern of seizure and brought to the PICU.

He, you know, he was, during the route, his tube had come out. He remained extubated. He was treated aggressively with IV fluids and IV fluid resuscitation. He made a remarkable recovery within 24 hours again. And then his presumptive diagnosis was severe acute gastroenteritis with hypovolemia, with possible sepsis. And then we were consulted for this patient because of mother's concern of possible cow milk allergy. She had stopped giving him in cow's milk and she stopped breastfeeding.

He was only on solids, beaning food, and was surprisingly doing well. He had no exposure to milk and dairy until that accidental exposure where the grandfather was babysitting the child, gave him a milk formula, because mother was away at work. So these patients, the clinical hallmark of these patients are they present with very dramatic clinical symptoms and also make a dramatic recovery. But if you're not aware of such entity, you're not likely to come up with this diagnosis.

So what is F-PICE? F-PICE is a food protein-induced enterocolitis, is a non-IGE-mediated food allergy characterized by delayed gastrointestinal symptoms following ingestion of culprit food. The hallmark is pronounced GI symptoms. And the symptomatology may manifest little late than usual, usually two to four hours or longer. As a result, the core relationship with that particular culprit food is often missed. But F-Pi's is a story of missed or delayed diagnosis.

Most of these patients have at least five or ten episodes before they are properly diagnosed. Otherwise, they are just investigated for other unlikely etiology diagnosis. There's definitely a low awareness amongst the primary care provider. A recent survey which looked at 100 odd patients with FPIs, when they did a retrospective analysis, how many of these patients had this diagnosis labeled prior to their referral?

Only 22% had proper labeling of the diagnosis. Unfortunately, FPIs, there's no diagnostic test available, so it always is clinical diagnosis. Many of these patients often have unnecessary diagnosis and invasive testing, particularly endoscopies, which is probably not necessary if you make this diagnosis early during the disease. You also have to remember, F-PICE is not necessarily a benign condition. The usual course is a spontaneous recovery with time, but 20% of patients like

this patient end up with severe hypovolemic shock. Now, recent rare cardiac arrest have also been reported, both in infants and older children. And this diagnosis is evolving. Your understanding of this disease is changing and evolving. We really need to learn more about this disease to do a better job in clinical management. So, how recent is this diagnosis? The first documented case, likely of F-Pi's, was published by two gentlemen, Gribosky and Powell, in 1970.

It was the case of infant with cow milk F-Pi's. The diagnosis was not labeled as F-Pi's, but thought to be a milk intolerance or probably a milk-induced colitis due to recurrent episodes of traumatic symptoms and improvement after cow milk was withdrawn from the child's diet. In 1970s, the disease was thought to be exceedingly rare and rarely reported.

However, over a period of time, there was sporadic increasing report of F-Pies, surprisingly to now not cow milk, but variety of solid food, including like rice, chicken, green peas. More reports were published for older children, so no longer it was necessarily a disease of infants. In 2012, a first documented case of scallop-induced F-Pi was reported in adult, proven with an oral challenge.

Recently, most of the food associated with F-Pi are thought to be innocent food, not the Big 8, which cause severe allergic reactions. But recently in 2020s, there's a new kid in the block. Peanut and egg have been increasingly reported as a cause of F-PIs.

We do not know a reason for this, but perhaps the new recent recommendation of infant food feeding guidelines, which recommend early introduction of even highly allergenic food, including peanut, in young infants between four to six months of age to prevent a development of food allergy. So early introduction of food, you develop tolerance to food allergy, but do you create a new problem? Are you going to see more F-Pi's in this patient? That needs to be elaborated properly.

So what the landscape of F-Pi's have changed from 1970s. Now we know probably any food can cause F-Pi's. The common ones are cereal grains, vegetable, most commonly sweet potato, carrot, fruits, and fruits like banana, avocado, apple, or other solid food, typically in older children, including seafood, peanut, nut, and eggs. What has changed in the literature? If you look at the curve of publication in a peer-reviewed journal, nothing was known until almost 2000, 2010.

It's only in the past decade or so, there has been a surge of scientific publication in peer-reviewed journal. Most of these articles are emphasizing on the clinical elements, what are the epidemiological aspects of FPI's, the clinical profile of patients, and many of them also have looked at longitudinal data about what is the outcome of patients with FPI's. None of them have touched on pathophysiology of FPI's.

I did talk to you about what is the quality of lifestyle for patients, a parent, or a caregiver with FPICE. And as a result of being ignored by the medical fraternity, the caregivers established an organization called FPICE Organization. It's established in the United States, but now it has a worldwide membership.

International FPIES is a non-profit organization which is dedicated time for patient advocacy and research funding with the purpose of increasing dissemination of knowledge about FPIES and educating caregivers and provide them the support they need to take care of children with FPIES. It's only until 2016 there's an ICD code for FPIES established.

Thus, the disease got a name, it got an established diagnosis, and now, even for research purposes, we could look back, do a retrospective analysis using this coding for FPIES. There were various diagnostic criteria proposed by different researchers, creating a lot of confusion. What is the right criteria for diagnosis of FPIES? Particularly so because FPIES is a clinical condition.

So all the experts came together and they published the consensus guideline in 2017 for diagnosis and clinical management of FPIES, which was the first scientific publication really facilitating clinical care of FPIES. It's only until 2022, a first NIH grant was offered to a Boston Children's Hospital group to study the pathology of FPIES.

In 2023, the Consortium for Food Allergy, which is an organization heavily involved in research in food allergy, now also included F-PiS under the umbrella for further investigation. So the future looks promising because there is more involvement of scientific community now to understand the disease of F-PiS and help with clinical management for our patients.

A recent publication by the NIAID group, a workshop report of FPIES was published in 2025, February, stating the current status and future direction in management of FPIES. So, what is the prevalence of FPI's in the United States? It is estimated 0.51% of the pediatric population may have a diagnosis of FPI's. That means there are about 375,000 children running around somewhere waiting to come to your office with this clinical symptomatology.

And hopefully we should not miss this patient with an erroneous diagnosis. The prevalence in adult population is about 0.22% estimated 550,000 of adults with F-Pi's. So it's reasonably not an uncommon disease. F-Pi's is prevalent worldwide. There's a significant variation in prevalence. More importantly, the food which triggers F-Pi's symptoms. For example, F-Pi's with soy is almost not reported outside the United States. In Japan, egg is the most common food trigger.

In the Mediterranean climate, like Spain, Italy, seafood is the most common culprit. In Australia, cereal grains is a common culprit. So there is a variation. There is an international drive about learning about this disease entity, and the International FPI organization helps coordinate this research work.

The impact of FPI is significant. It can cause a severe effect on the growth of a child, largely due to eating disorders that China might develop because of delay in introduction of solid food.

Also, avoiding nutrient-dense food can result in nutrient insufficiency, causing growth alteration. So you have to remember this impact of FPI's in development of an infant. The most important effect we talked about is the quality of life. There is significant impairment in the mental health of a caregiver, increase occurrence of anxiety, stress. Poor quality of life, and decrease self-efficacy in taking care of children with FPI's.

Of course, it creates a lot of financial burden because often the parent have to lose their job, stay home to take care of the child, and look for alternate, more expensive types of formulas or diet, causing a significant financial burden. In fact, a recent study showed that the health quality of life of caregivers of children with F-PIs have much worse quality measure compared to caregivers of children with food allergy in all domain and also in specific domain of measure of quality of life.

So therefore, it's a silent disease causing problems which need to be recognized. And that also should be a part of our care to make sure the mental well-being of the caregiver is taken care of. How do you diagnose F-Pi's? Pavel was the first person who associated the food trigger causing F-Pi's. So if you give that culprit food, you have symptoms, you remove the food, your symptoms are improved, and at a later time, if you reintroduce the food, the symptoms reoccur.

So there are numerous other diagnostic criteria established by various authors.

In 2017, the International Consensus Guideline published the first consensus criteria for diagnosis of FPIES. So this criteria essentially was clinical, and that's important because FPIES is a clinical diagnosis. You need appropriate clinical criterias to make this diagnosis. The guidelines recommended for diagnosis of FPIES, you need to have two major criterion and at least three of the minor criteria.

The two criteria are occurrence of symptoms, delayed GI symptoms within one to four hours after ingestion of suspect food. Most importantly, it is not an anaphylaxis, it is not an IgE-mediated, so there should not be any evidence of an IgE-mediated reaction like HISE. Angioedema, cough, throat closure symptoms, and other significant systemic symptoms. The minor criteria are much more fulfilling for a severe manifestation.

Like if you have a presentation of hypertension, hypothermia, a patient to be seen in an emergency room, requires IV fluids, or has extreme lethargy and pallor, the diagnosis becomes pretty easy if you know about the disease entity. If you have another episode in the past, then your suspicion is significantly increased. Or if the patient has another food trigger for FPI symptoms, the diagnosis might be easier. This diagnosis criteria work very well for severe FPI's, but I have my reservation.

Patients with milder form of FPI's might be missing, will not be diagnosed by using this criteria. And there is a spectrum of patients with milder phenotype. The most important thing is the patient, apart from this acute illnesses, are normal and well-growing infants without any other problem, as long as the offending food agent is avoided. There's also an entity called chronic F-Pies. This is a little wishy-washy. There's no clarity on this.

Largely, it states that the symptoms are long-lasting. It could manifest as a severe presentation where the offending agent is not avoided and ingested on a regular basis. A child may have a persistent and a progressive vomiting and a diarrhea, often with blood, sometimes with dehydration and metabolic acidosis. A milder version of these chronic F-Pies may have intermittent episodes of vomiting and diarrhea.

The most important thing is patients with chronic F-PIs will definitely have poor weight gain, failure to thrive, even without dehydration and metabolic acidosis. So that's a marker if you're dealing with a patient with chronic F-PIs. But I believe many of these patients will be worked up more for malabsorption or a chronic gastrointestinal disease before we might think about chronic F-PIs.

Other important criteria is even after you withdraw the incriminating food agent, the recovery is not rapid.

It may take three or ten longer days for the recovery to occur. Many of these patients with chronic F-PIs are properly diagnosed, and if you reintroduce that culprit food, they can manifest as an acute F-PIs. So, the phenotype might change after avoidance of food for a long period of time. Chronic F-Pi, some of the important highlights are, is almost never seen outside the infancy age group. It has not been reported with solid food.

Exclusively, it's related to cow's milk and soy. So that at least is a little less concerning feature. At least we would be able to diagnose F-Pi in young infants. But the common story is there's often a delay in diagnosis resulting in a prolonged and progressive course until the food is eliminated. So the guidelines have tried to establish a clinical profile based on the symptomatology to identify are there any particular phenotypes in the clinical observation of all the cases.

When they reviewed the literature and looked at all the case reports in the case series and the case cohort studies, they wanted to find out a pattern. Is there a certain clinical characteristic which you have? Does it affect the clinical outcome and the course of the disease? So that's called phenotype. Any observable clinical features which can be identifiable and can be correlated to the endotype or the pathology of FPI's. So broadly, they propose four different phenotypes for FPI's.

One, depending on the age of onset. So there's a different outcome for patients who present early the nine months of age compared to more than nine months of age. Definitely the older children and adults have a different profile and outcome in terms of their FPI disease.

Other phenotype was based on the severity. like a lot of these patients we present with a very severe presentation like the one I presented or could be a milder version that again based upon like we talked about acute versus chronic F-Piase. There's another entity observed in this phenotype evaluation.

Patients had IgE positivity. That means the skin prick test or the serum IgE test for the food was positive. This was called as an atypical F-Pi. So about 5 to 30% of the patients with F-Pi can have a positive IgE test. What it showed that these patients with atypical F-Pi generally had a protracted, sometimes unresolved course. That means the disease symptoms really lasted for a longer period of time.

And not surprisingly, about 25% of patients developed true type 1 or IgE-mediated allergic reactions. So is this indeed a separate profile? Or as we have learned over a period of time, not only the prevalence of F5s has increased, but also the IgE-mediated diseases like allergic rhinitis, atopic dermatitis, allergic asthma, So is this a cause effect or this is just the two entities being observed together is not known.

So, a typical phenotype of an infant FPI would be an infant with cow milk and soy is likely to present before six months of age. If they're present earlier than that, they are likely to have more of lower GI symptoms like diarrhea, including blood in the stool, and likely to have failure to thrive. Most of the FPI food symptoms occur with a direct feed, meaning the child has to eat the food to develop symptoms. and typically would occur in the initial introduction.

Most studies show that manifestation of FPI have occurred within the first four to eight initial feeds. So that's a little comforting. If a child has been eating food at least 10 or 12 times or more, it's less likely to develop FPIES. A solid FPIES manifest a little later in infancy, between 6 to 12 months of age, with a mean of 5 to 7 months. Most solid F-Pi's, the common food is cereal grains. Rice and oat is the most common in the United States.

Other solid F-Pi's are fish, egg, and poultry. Usually chicken is considered to be low-allergenic food, but chicken F-Pi's are much more commoner than other poultry. F-Pi's in older child and adult, increasing reports of F-Pi's in older age group. Most present with F-Pi's, acute F-Pi's, chronic F-Pi's almost not known in older child or adult. They typically manifest with symptoms with predominant abdominal cramps or pain. That's a very common symptomatology.

Nausea and vomiting is also accompanying these symptoms. So often these older children or adults will be misdiagnosed.

Sometimes you would think it's a foot poisoning or foot intolerance and may not pay attention that this indeed could be an F-wise. The key observation with findings was, is more common in female population. Again, same old story, misdiagnosis, until the patient had anywhere from 6 to 15 episodes. Definitely, it's much more persistent. Very few are likely to develop tolerance over time.

Incidentally, there was higher rates of comorbid GI conditions like irritable bowel syndrome or celiac disease in this patient population. The most common foot trigger is shellfish, mollusk, or fish. So seafood are the most common, followed by egg and also mushroom. Many of these patients might be misdiagnosed as mushroom toxicity or poisoning. So be mindful of that. So what are the food triggers for F-Pi's? Virtually any food is possible trigger.

It varies with the geographical variation and the dietary habits of that area. Most common are the single food F-Pi's, amounting average around 60% of the patient population. However, the single food F-Pi is not so common in the United States. Usually two food, a cow milk or a soy with oat or a rice seems to be the most common combination in the United States. Some of the patients, almost 10% of the patients can have multiple food F-pies ranging from 2 to 13 food in a bad situation.

We do not understand the risk factor for multiple food F-pies. A small study of Australian infants showed that if the infant had a reaction very early age or if they have F-pies to fruit and vegetable and rice, more likely to develop multiple other food F-pies. So just to recapitulate, I mean, acute F-Pies in the United States, the common triggers are cow's milk, soy, grains including rice and milk, egg, fruit, and vegetables.

In Europe, it's cow's milk, fish, egg, grain, soy. In Australia, rice, cow's milk, egg, goat, and poultry. Chronic F-Pies, just infant formulas. That's it. Interestingly, many food co-associations have been noted in children with F-Pies. For example, if you have cow milk F-Pi's, almost 40% chance you'll also react to soy. So that's not a good substitute when you have a cow's milk F-Pi's. The probable alternates are either extremely hydrolyzed formulas or amino acid-based formula for infants.

If you have solid food F-Pi's, there's almost a 45% chance you may have another solid food F-Pi's is the observation. These are earlier studies. So I'm sure this co-association may be different with time, as we know about more study on this aspect. If you have F-Pi's to grain, more likely you'll react to another grain is up to 50%. Similarly for poultry, almost 40%. So if you have F-Pi's to chicken, turkey, quail, and whatnot would not be a good alternative.

What about F-Pi's in a breast-fed infant? So there's very limited data, but clearly it's very, very uncommon. In fact, the European Academy of Allergy Immunology and our American Academy of Allergy Asthma Immunology have put out a position statement stating that it's uncommon to see F-PYs in exclusively breastfed infants. There is no need to recommend any maternal allergen avoidance in asymptomatic infant. Rarely, an exclusionary maternal diet might be effective, but generally, not recommended.

So be careful when you're seeing a patient and your suspicion is F-Pi's. It's not likely because of the breastfeeding. It could be some other agent which you have not recognized.

What is F-Pi's pathology? What do we know of? All I can say, we really don't know anything about it. I could just say that and move to the next slide. But I'm just going to recapitulate a few things which is thought to be probably a proposed mechanism. It's clearly an interaction between the immune system, the GI tract, and autonomic nervous system.

Although we do not know the exact details. It is presumptively thought that there is some disruption in the intestinal barrier which causes leak of the protein, activation of local immune system. There's a big role for neuroimmune system there, which triggers signaling of the vagal nerve, triggering the vomiting center in the brain. If you're a lot of vomiting and diarrhea, you're hypovolemia. That activates the autonomic nervous system to maintain the homeostasis.

So we really don't understand very well There is no evidence of any systemic inflammatory changes. For example, in patients with food allergies, you can identify IgE in the blood, or you can find some T-cell clones specific to that food antigen as an evidence of food allergies. But none of that is evident in the blood of these patients. So the best explanation is there is some local inflammatory process.

Probably innate immunity plays an important role, including monocytes, macrophages, and neutrophil. The stress causes release of cortisol, causing increased margination of neutrophil in the blood. And that's what you see as neutrophilic leukocytosis. There is a significant proliferation of lymphocytes, but it's a pan-T cell activation, meaning there's not one type of T cell. It could be Th1, Th2, Th17, Th22, which are all involved in inflammatory responses in the gut.

Perhaps there's a role of mass cell also. But what has been shown that serotonin probably plays an important role in clinical manifestation of F-PIs. Serotonin is a mediator released by specialized cells in the intestinal epithelium called enteroendocrine cells. The receptors for serotonin is a 5-HT3 receptor, which is expressed in multiple cells, including lymphocytes, macrophage, immune cells, intestinal epithelial cells, which are important for fluid and ion exchange across the epithelium.

On the afferent nerves of spinal cord, vagus nerve, which are important mediator of vomiting sensation. So serotonin has a role in GI motility, when I say GI, gut secretions, gut motility, perception of nausea, vomiting, and abdominal pain. I'm saying so because there is one drug which is now used to treat FPI's acute symptom called ondincetron, which had been used for longest time to treat vomiting with chemotherapy or even gastroenteritis.

But this drug had been used for FPI's and in acute FPI's symptoms seem to dramatically resolve with use of ondincetron. So perhaps because it's a serotonin receptor antagonists. So probably there's a big role for serotonin, which needs to be looked at carefully in pathophysiology of F-PIs.

How do you diagnose F-PIs? There are no laboratory markers. There are no lab tests to confirm F-PIs. It's essentially a clinical diagnosis. But you could probably do what is called an oral food challenge, which typically is done by allergists in their office. It is a medical procedure in which food is eaten slowly in a gradually increasing amount under medical supervision to accurately diagnose or rule out true food allergies.

So we commonly do this for our patients with IgE-mediated food allergies. It's very challenging. It's very difficult. It's very resourceful when it comes to doing oral food challenges for F-PIs. It is fraught with risk. It requires hospitalization and an IV fluid access. All of that makes it a very problematic procedure. So it's not commonly done. You will have very few centers who actually perform oral food challenges for FPI's. Many of them are research center.

Do you really need to do oral food challenges for patients in FPI? If the diagnosis is very compelling, you really don't need to. But there is utility of oral food challenges, particularly when the history is unclear and when you're considering to introduce new food. A lot of these patients are, caregivers are extremely anxious. They're worried about introducing any new food in spite of reassurances. So perhaps they would want an oral food challenge before you can introduce a new food.

Obviously, it's very important to determine whether the disease resolution has occurred. So these are the two areas where there's a big role for oral food challenges. Obviously, you have to sit down and discuss with the patient and caregiver. It's always going to be a shared decision because of the risk involved in performing an FPI. There is no established accepted protocol. This is an example of oral food challenge. Obviously, it's only done under supervision of an NMD with an IV access.

You need to continuously monitor the vital signs. The initial step includes administration of protein in a quantity of 0.06 to 0.6 kilogram of the body weight in a three equal doses. You should not exceed more than three grams of total protein because of fear of severe reactions. You have to wait at least for two to three hours and then the second step would be administer age-appropriate serving of that particular food and then monitor for further six hours.

So, invariably, you need to hospitalize this patient for observation. More than 50% of patients will get a serious, severe reaction if the challenge is positive, requiring IV fluids and multiple medications. So, bottom line, oral food challenges are not easy to do, not easily performed, not many people are doing it, but always a consideration when the need is appropriate. What do the management FPI's include?

Essentially, a management of acute symptoms, depending upon the severity, IV fluid resuscitation, and administration of ondincetron has significantly improved outcome of patient during the acute manifestation. Just like epinephrine is necessary for anaphylaxis, ondincetron is necessary when your clinical suspicion is acute FPI's. You should be observing this patient at least for six hours after the last clinical reaction before being sent home.

And they should have a normal clinical symptomatology before you would send this patient home. We talked about Onel syndrome. It's only recommended for infants more than six months of age. There is no safety data for younger infants. It can be administered orally at home, IV intramuscular. Although it's a very promising drug, it's poorly studied in this patient population.

You have to be mindful of cardiac disease, particularly if they're prolonged QTC interval, arrhythmogenic effects of Andres syndrome have been shown. Also, patients who are taking certain drugs which can prolong QTC, including a variety of antifungal macrolite antibiotics, should be a consideration. All patients with FPI should get a home action plan, just like we have asthma action plan, anaphylaxis action plan. FPI's patients should also get a plan to take care of reactions at home.

Particular patients with a severe previous reaction, activating EMS services is important and early, even though they might have given oral on the syndrome to curb the symptoms. Most patient moderate symptoms should go to ER. Patients mild symptoms, that means one or two episodes of vomiting, no lethargy, and in the past had recovered at home, probably could stay home and continue with vigorous oral rehydration.

What is the long-term management of F-PiS? Essentially, avoid, avoid, avoid primary trigger. Food elimination is the essence of treatment of F-PiS because you don't want to keep provoking this clinical reaction. Continued reassurance, monitoring for growth and development. You can need to seek advice of a nutritionist to provide a proper complementary diet for the infants. Enrolling in a peer group support services like the International FPI Organization is a great idea for patients with FPI.

All these patients should be periodically evaluated for IgE sensitization or for consideration of oral challenges. There are some empiric guidelines, not based upon solid evidence, but on expert opinion, which recommend how you can introduce a variety of weaning food in young infants. You need to select low-risk food like vegetables, fruits like blueberries, strawberries, or meat like lamb, or cereals like quinoa, or other millets.

Tree nuts and seed butter seem to be more tolerant in patients with F-PIs, and particular appropriate age group. The guidelines recommend that any new food introduced should be given over a period of five to ten days. So an example of a new food introduction could be, start with one fourth teaspoonful at 9 a.m. Repeat after 6 hours. You need to wait for 6 hours because that's a time period of clinical manifestation of FPI's. And the next would be 6 hours later of double the size.

Keep doubling the size in consequent days until the child is able to eat appropriate portion. The natural history of FPI's is in 60 to 70% of patients will have resolution of the symptoms spontaneously. We do not have a good data about solid FPI's. Atypical FPI's do not resolve timely. So there are numerous clinical retrospective studies looked at time period of

resolution of clinical symptoms with specific food. For example, Kobe et al. Reported that patients with cow milk allergies about 5.1 had a resolution. Sorry, patients with cow milk allergy had a complete resolution by five years of age. Soy, 6.7, rice, 4.7, and so on and so forth. So, there's a different population. The outcome has been different. But it is expected most patients with classic FPI's would make a recovery with time.

Of course, when we know some things, we do not know a lot of things. And there's a long list of things we really don't know, which is a problem. Because these are the various unmet needs of patients with FPI's.

Be it for identifying the phenotype, knowing the triggers, knowing the diagnosis and proper management and understand the psychosocial impact of patient for the caregivers. So essentially, to just summarize, I want you to be alert and be able to diagnose patients with F-PIs, particularly patients who present with medical emergencies. It is always a challenge, going to be a challenge, to diagnose patients with chronic F-PIs. There is no diagnostic laboratory test you could do.

It has to be a high index of clinical suspicion to make a successful diagnosis clinically of FPI's. It is important that you recognize this entity early in the child's life to improve their long-term outcome and to get appropriate recommendations. You need to seek help of nutritionists and support organization to improve the comprehensive well-being of the caretaker and the child. These patients need to be monitored periodically for consideration of overall food challenges.

It's an evolving science. You'll have more information with time with better criterias and recommendations for clinical management of F-PIs.

With this, I'm going to end and I will be happy to take any questions. I appreciate your attention. If anybody wants to send me questions as an afterthought, I put out my email here, mpansari at dmc.org. I'll be happy to respond. So how many of you have seen patients with F-PIs And what was your clinical experience? Can somebody chime in on that? And, of course, I'm ready for your questions, if any. Thank you, Dr. Pansari, for that.

Introducing us to the new concept of FPI's. Let's see if anybody has any questions, comments. They can either put them in the chat box or they can ask you directly. So I have a question. Yes. I actually have experience, not personally. I mean, with someone having F-Pies, which is why you described it perfectly in the opening case. I was like, okay, that's it.

But I'm thinking that if it's not milk or something that could need to be a part of your life often, what most people would do is avoid the trigger. And they wouldn't feel that it would be important to re-challenge themselves because they could just avoid the food. The food that I had... Experience with the patient and with sweet potatoes. And so they're successfully able to avoid sweet potatoes. And I don't think they feel like going through that vomiting,

bloody diarrhea, kind of shock-like experience. And so they can do that. But I think it really then is a comment on you don't really know how often this occurs or resolves because there are a certain number of people that, you know, are out there and you just, they're just not going to re-challenge themselves. Yeah, absolutely right. I mean, that's a very judicious comment.

Exactly. That's what happens in real life. Patients, particularly if they have seen a doctor who could not establish this diagnosis, if there's no name tag given to it, they are always confused and they know this food has been causing me a problem. Why should I be re-exclosing my child to go through all that trouble. So they would just continue to avoid that. And until they meet a person who could reassure them, you know, things change with time, maybe we can reconsider.

It's a matter of getting the confidence and talking to them, explaining to them what usual outcome is with whatever little we know, perhaps would change their mindset. But there's no way any parent is going to just say, I know I'm going to try this again because they know you like it or not, doc, I'm not going to listen to you. This is my experience. You tell me whatever. I'm not going to do that. And this is exactly what happened to us. We have some certain patients.

I don't know. I may have four or five patients only in my practice. And two of them, I wanted to do a challenge. But they say, Doc, I don't want to do it now. Maybe when the child is older. It's another way of telling me I'm not interested. They don't want to tell me, no, I don't want to do it. But I totally understand that. So there is a role of oral food challenge for such patients, but whether they will be willing to do it. Because oral food challenge is a supervised test.

It's a medical, sort of a medical procedure. So at least that benefit they will have rather than, you know, go eat at home, which they never would do. So, yes, but we have to keep talking about this, reassuring a patient, know them, this is what you have. This is what is expected to happen in spite of our limited knowledge. But, you know, that might change their mindset and perhaps, you know, they might be willing to do re-exposure. And thank you. Excellent talk. Thank you.

I will come back to you, Dr. Brooks, but there is a question in the chat box. What are stool calprotectin and stool alpha-1 antithypsin levels in stool during the episode of. F-PIs? So, there's a limited information in that at all. So, these are like acute phase reactant in the blood. People have noticed with inflammation in the gut, certain markers are released. But nobody has looked at particularly using those two proteins to look into the stool.

At the most, people have looked at stool eosinophils, stool leukocytes and whatnot. But F-PIs, nobody has done biopsies for patients with F-PIs. Obviously, you're not likely to do it because it's such an acute manifestation and dramatic recovery. You are not likely to do any endoscopy and biopsy for this patient. Maybe for chronic F-PIs because you want to rule out other gastrointestinal disease.

So, we really don't have a data. Whatever few times people have done endoscopy, all they have found was nonspecific changes, some sort of damage to the villi, but nothing observable. Observable. So also, there's no evidence, bottom line, of looking at these two items as inflammatory markers in F-Pi's. Whether F-Pi's is an inflammatory disease, we don't know. But once we learn, like I said, there was a recently NIH grant trying to investigate the pathology of F-Pi's.

Perhaps once we know better, people will start looking at different markers for F-Pi's. But that's an excellent thought. I mean, that's a very astute observation. Is there a role for such stool studies? Thank you, Dr. Panster. Dr. Brooks, go ahead, ask your question or make a comment. I just want to thank you for an excellent description.

I was first introduced to this disease when I was a fellow in allergy immunology some years ago, and the child was worked up for a bloody gastroenteritis by gastroenterology. We finally determined he did have a milk allergy and resolved. And back then, we called it allergic gastroenteritis. And I took it upon myself after he was a year or two to do an oral challenge, and he had exactly what you described.

He had a massive bloody diarrhea about an hour or two after the challenge and became pale and hypotensive and lethargic. So I'll never forget this disease. So thank you so much. I can guarantee you're not going to forget because you see this once, you're going to remember it lifetime.

And you really want to, you know, you will feel more curious about this disease because really it's unfortunate that these patients out there without any labeling and they do not because they're not labeled and they're not told what can potentially happen which is a very risky proposition Thank you Dr. Pansari for that fascinating presentation I really appreciate it Thank you all for attending this morning's Grand Round, I'm going to conclude and see you

all next week Friday at 7.30 in the morning Thank you all Thank you Dr. Pansari Bye bye Have a good weekend, good Friday Enjoy the cheese. Don't forget to click on the link in this podcast for free credit. That may include CME, MOC, or ethics credit, depending on our topic or podcast. Music. Pediatrics Now is brought to you by University Health's new Women's and Children's Hospital and the Department of Pediatrics at the University of Texas Health Science Center at San Antonio.

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