Allergy Nutrition

I first published this post on my blog last September, when I began to do further research into my son's FPIES.   I started with Allergy, with one of my favorite resources at that time (remaisn a top resource):
Vickerstaff Health Services


Janice Joneja Vickerstaff, PhD, RD is an inspiration for me. I had the privilege of hearing her speak at a Nutritional Peds conference a few years ago, her discussion on allergy’s intrigued and inspired me.  I bought one of her books on “Dealing with Food Allergies in Babies and Children” right away, and hungry for more information, I also bought another one of her Allergy books. I have also since bought Digestion, Diet, and Disease to learn more about gut health from her perspective. I find her books very easy to read and follow, and full of valid medical information; so have utilized it as a resource time and again.

I’d like to explain more, from my understanding of her books. I will be using her words for much of it but not always directly quoting all of it- I merely want to provide an overview/synopsis/outline of the pertinent information to this “type” of allergy. 


“Reasons that one child’s body responds to food by developing distressing symptoms and another uses the same food for comfort and nurture may be found in several factors”.
1. Child’s inherited genetic make up.
2. Circumstances within first food encounter
3. Microorganisms that live in child’s GI tract
4. Medications take by mouth, or exposed to (such as mothers milk)
5. Other factors research is only beginning to understand.

“Food sensitivity is unlike any other disease entity….any food is capable of triggering an allergic reaction to a child who has been sensitized to it, or lacks the systems required to process it adequately when it enters the body”.

What is the mechanism for food allergy? And how could this relate to FPIES?

When an allergen enters the body of a person at risk for allergy, an extremely complex series of events “set in motion that will finally result in the release of chemical (called inflammatory mediators) that act on body tissue to cause the symptoms of allergy. All immunological processes involve the various white blood cells (leukocytes), and different type of chemicals they produce”.

First step: the body recognizes the invading antigen. “An antigen is a protein within the cells of any living material that enters the body. When an antigen causes an immune response, it is an allergen. When the antigen enters the body, the white blood cells (lymphocytes) are activated. Lymphocytes are the first cells of the immune system that recognize and respond to anything foreign entering the body (sentinels of the immune system)”. There are two types of Lymphocytes in the blood: Tcells and Bcells. Tcells are the ultimate gatekeepers and controllers of the immune system. “Th (helper T cells) are responsible for identifying foreign materials that enter the body. Th cells initiate and direct the subsequent activities of the immune system if foreign material is deemed a threat…. T Cells exert control by means of messenger chemicals, cytokines”.

The response to cytokines is Th1 or Th2 and this response controls the way the body reacts. “When a pathogen (disease causing microorganism- virus, bacteria, other foreign material) enters, the immune system protects the body by a Th1 response (IgG). Cytokines are produced and stimulate the formation of antibodies of the IgG class which destroy the invading microorganisms by means of the complement cascade…symptoms such as fever, aching muscles, fatigue, malaise (much like the flu) are the result of the body’s response to cytokines and other inflammatory mediators produced during this battle between the immune system and foreign invader”. “The complement cascade is a group of over 20enzymatic proteins in the blood that act together in response to antigen and antibody to destroy foreign cells by splitting them apart (lysis); this process releases various chemical byproducts that act on opsonin’s, chemotoxins, and anaphlatoxins to help destroy a threat to the body and results in inflammation in various tissues.”

So, if FPIES is an IgG response, it is the Th1 response that is activated. It sees the food as a foreign substance – in the same way it would see and attack a virus or bacteria.

Th1 response protects the body from disease, and the IgG antibodies are responsible for the ultimate destruction of the invader. The Th2 response results in allergy, IgE antibody.

So, if Th1 is the first line of defense against IgE, FPIES is an overreactive Th1 response 

Some evidence that allergy is inherited… “the characteristic inherited is the potential to respond with a Th2 response when harmless foreign materials enter the body…. Some suggest Th2 is more primitive response than Th1 and as baby matures, the potential for immune system to respond with Th2 is gradually diminished. This decline, together with the maturation of the digestive tract (that provides a barrier between food molecules and immune cells) would explain why children outgrow their allergies”.

What is Oral Tolerance? “Oral tolerance is a term to indicate that although the immune system of the digestive tract can recognize that all the material we consume as food is completely foreign to our bodies, a tolerizing event has occurred that has taught the T cells that the foreign material is harmless and can safely enter the body”.

Something is askew in the FPIES child that the T cells perceive this as a harmful substance; they are taught to remember that it was originally perceived as a harmful substance; each subsequent ingestion has more T cell memory (army) to fight this perceived invader.


All food is foreign to the body (upon first ingestions)….what is it that allows food to apparently evade the barriers of the immune system in a normal child vs. an FPIES child that food is perceived as invaders to the immune system?


Immune System and Digestive Tract
The Immune system of the GI is different than other parts of the body, it is called the GALT- Gut Associated Lymphoid Tissue. “Processing of food through this system allows the uptake of nutrients through the digestive tract walls without triggering the protective response that would otherwise form a barrier to the foreign materials in food. At the same time- any virus or bacteria taken in through the digestive tract are effectively excluded by the GALT. We have a system that can- at the same time and in the same place- recognize and differentiate foreign materials that is safe (food) and foreign material that is a threat (microorganism, toxins….).”

So, is FPIES a breakdown in the GALT? A deficiency mechanism, or an over reactive one?


“But that isn’t the whole story, the GALT must also distinguish between invading microorganisms and other permanent residents of the large intestine- gut microflora”. And many moms have suspected/known their little one’s microflora is “off”. “Microorganisms in the large intestine defend the bowel from invasion by harmful microorganisms by competing with them for space and nutrients; also keeping surrounding tissue healthy by stimulating the GALT in a positive manner”.

Process of Tolerance:
“The process of oral tolerance involves the T cells and their “messenger chemicals” cytokines. T cells that first encounter the foreign food when it enters the very first time (breast milk or solid foods) are of the Th1 type (Th3 immunological protection). Food molecules are picked up by special cells in the infants digestive tract. The antigenic parts of the food (proteins) are then “presented” to the T cells where they couple of special receptor molecules on the T cell surface”.

“T cells with attached food molecules are then transported on the lymphatic system to the thymus gland. There, the regulatory T cells (Treg) stop any further action on the part of the Th1 cells when it is discovered that the “foreign molecules” pose no threat to the body. This process of inhibiting T cell action is carried out by cytokines especially TGFβ(Transforming Growth Factor-Beta) and possibly IL-10 (Interlukein 10).”

Is there a deficiency in the cytokines (such as tumor necrosis factor, transforming growth factor, or IL-10) that inhibits this regulation to happen in the FPIES child?

“The ‘educated’ T cells are then transported in the blood circulatory system and back into the digestive tract GALT as “memory cells”. Is this where the reactions become full body? Eczema, itching, thrombocytosis, angioedema, etc. leading up to a trigger reaction, as the T cells make their way through the body and back to the GALT and now have memory cells to attack with future ingestion's (the delayed-“build” response some of us see)?

FPIES is a Th1 response- the body sees food proteins the same as disease causing microorganisms ; there is a skew in FPIES kids bodies T cell response- Th1 is OVER REACTIVE!

IgE allergy = B cell lymphocytes= Th2 response =produce IgE antibodies


Non IgE = T cell= over reactive and does not proceed to Th2 response (thus preventing IgE food allergy- actually protecting the body- as it does for viruses/bacteria).

FPIES is a skew/”mis-fire” of the Tcell action….the food proteins should be going through the Th1 as “foreign but safe” and to the Th2 responses and either producing antibodies (IgE) or continue on as safe (already passing Th1 gate keepers). But with FPIES, the food proteins go through the Th1 response and get picked up there as foreign and perceived threats; the immune response is not initiated because it is begun in the non-immune Th1 response- it is attacked before it gets to the Th2!


-White blood cells aid the immune system in recognizing foreign proteins.
-T helper cells produce characteristic cytokines.
-Specific cytokines determine response – Th1 protection vs. Th2 Allergy vs. Th3 Oral tolerance
Food = white blood cells recognition =Lymphocyte = T cells= Th cells= cytokines= protection vs. allergy. FPIES is a disruption in the Th1/Th2 response.

Antibodies in food allergy
IgE= recognized typical food allergy response, but there are other antibodies in food sensitivity. IgG is being recognized in Celiac gluten sensitive individuals. IgG is also thought to be what FPIES response is related to, although isolating the specific levels with other factors has not been achieved for FPIES. IgG is not yet a reliable test for food allergy.
“IgG antibody can be found circulating in the blood of people who have no signs or history of adverse reaction to foods. In fact, some think that an increase in anti-food IgG in some cases may be indicative of successful resolution of IgE mediated allergy. IgG mediated allergy remains complicated because of the nature of the antibody and the immunological reactions associated with it”.

Present knowledge (IgG):
-4 classes: IgG1, IgG2, IgG3, IgG4
-IgG4 subclass high affinity for food antigens
-IgG4 may be associated with milk allergy, in particular milk protein B-lactoglobin in atopic dermatitis (eczema) in children.
-Some evidence that total (all 4 classes measured together) might represent some protection from IgE
(again showing that a good IgG response is actually protective for IgE allergy)
-Food allergy in infants frequently associated with increased gut permeability “leaky gut”

Leaky Gut
"Antigenic food molecules passing into circulation trigger production of anti-food IgG. Thus, in cases of IgE-mediated food allergy that results in inflammatory reactions within the GI tract causing non-intact digestive epithelium, it is logical to expect to find higher than normal levels of anti-food IgG. Some think that these anti-food IgG antibodies represent a protective mechanism, rather than a source of allergic pathway”.


Conditions that predispose to allergy:
1. Immaturity of Infants Immune System – Immune system elements are in place at birth but do not function at levels to provide adequate protection against all infection. Antibodies are a fraction of an adults and secretory IgA (sIgA) the first line of defense of mucous membranes is absent at birth. Babies can have impaired or delayed maturing of various functions including cytokine production.

2. Permeability of digestive tract “leaky gut” – Infants intestines are highly permeable particularly 6-12mo.(become mature by 3yrs) and can absorb large molecules of foods that trigger the Th2 response.

3. Breast feeding – “breast milk provides the ideal nutritional, immunological, and physiologic nourishment for all newborns. Components of human milk enhance the baby’s natural defense and promote maturation of the immune system”. There is data that indicates the breast milk of atopic (allergic)mothers differs immunologically from that of non-allergic mothers. Atopic mothers tend to have higher levels of the cytokines and chemokines associated with allergy in their breastmilk. In addition, they tend to have a lower level of cytokines known as transforming growth factor (TGF-B) that promotes tolerances of food components in the intestinal immune response.

FPIES terms

This is the beginning of a few posts that I am attempting to put together to break down the FPIES processes, from how I see it through research on FPIES studies, Non-IgE food allergies as well as digestion and immune system responses. 

My disclaimer that this is FPIES specific, there are dozens (ok hundreds, millions?) of processes that can happen in the immune system and GI that may share mediators with FPIES; for example (and for simplicity?), I will not be going into everything a Tcell is responsible for- but how it (theortically) affects FPIES kids.

Terms & Definitions:

Antigen: Foreign substance that will produce an immune response.

Oral Tolerance: Specific supression and balance of the immune system towards an antigen.

Lymph nodes: Act as traps, or filters, for the immune system.  Antigens are presented via the lypmph nodes.

Peripheral blood mononuclear cells: Lympocyte, monocyte, macrophage. Critical piece of the immune system to fight invaders.  Lymphoctes are: T cells, B Cells and NK cells.

T-cell Lymphocytes: White Blood Cell's called the control cells (gatekeepers), classified according to markers on their surface (T-cell receptors- TCR). (T stands for Thymus, which is where they are regulated).  Each Tcell has a specific receptor for each antigen.

T memory: cells to store the memory of the molecule the body classified as an antigen. Numbers quickly expand upon reintroduction of antigen.


T Regulatory cells (Treg)- Tcell lymphocytes involved in preventing intestinal inflammation, and regulating oral tolerance. Receptors can be either alpha/beta or gamma/delta, each receptor is responsible for recognizing foreign antigens and designating either induction or suppression.

T cells are classifed into 2 subsets:
CD8- (suppressor) monitor for antigens in the body to destroy.
CD4- (helper) responsible for cell and antibody mediated immune responses.
Subset of CD4 are T-helper (Th) cells:
1.Th1- cell mediated responses,  regulation of defenses against bacteria, virusus, fungi, parasites. This process involves dendritic cells presenting the antigen to the Tcell and the T cell releasing cytokines which leads to the inflammation from recruited leukocytes to the site. 


2. Th2 - Involves B-cells, and promotes antibody production (IgE allergy).

3. Th3=responsible for immune regulation of Th1/Th2, which gives us oral tolerance.

4.Th17- more recently discovered found in the lining of the GI tract and skin, responsible for clearing out fungi and bacteria (gut flora) with inflammation.

Each Th cells produces different cytokines involved in the immune responses. 

Cytokines: Inflammatory mediators, responsible for the interaction and communication between cells that trigger inflammation and respond to infections.  These include  interleukins, lymphokines, tumor necrosis factor and the interferons.

Tumor Necrosis Factor (TNF): pro-inflammatory cytokine that induces death (necrosis) through the inflammatory process (controls responses by inflammation). Inflammation can be a protective measure- but it needs regulating (or you have auto-immune disorder of the body attacking itself).

Transforming Growth Factor (TGF-B1): Anti-inflammatory cytokine, a regulator of homeostasis of inflammation in immune responses.

Gut Associated Lymphoid Tissue (GALT): Digestive tract is equipped with it's own unique immune system. It consists of: tonsils, adenoids, Peyer's patches, lymphoid tissues, lamina propria. Everything taken in via the oral route is processed here for either rejection or tolerance of the immune system.

Peyer’s Patches: facilitate the generation of an immune response within the mucosa.

Lamina propria: connective tissue coating on intestinal lining (between surface cells and membranes of intestinal lining), part of the mucous membranes of the GI tract.

Toll-like receptor (TLR): receptors that recognize molecules from microbes that come in through skin and intestine and activate immune responses.

Dectin 1 agonist: works with Toll-like receptors in recognizing microbes.

Non-IgE food allergy (NFA): cell mediated response to food antigens.

New Guidelines for the Diagnosis and Management of Food Allergy in the United States

In December of 2010, the New Guidelines for Diagnosis and Management of Food Allergy in the US was released from the National Institute of Allergy and Infectious Disease, a component of the National Institute of Health.  The guidelines were developed over a 2yr.period with combined efforts from an Expert Panel from 34 professional organizations, federal agencies,and patient advocacy groups.  The full report can be viewed here: The Journal of Allergy and Clinical Immunology 

The full report is 84 pages long.   The first glance I took of it, of course I skipped through to where it mentions FPIES.  Yes, that is right- it gives an entire section for FPIES.   It is a very real diagnosis and having it mentioned here in the new guidelines for food allergies is a big step for the future of these children affected by it.   But the report is, of course, not limited to FPIES.   I have begun to read through it and am impressed with the information it provides, updated information that is needed as this country's food allergies are on the rise daily.   In fact, that is one of the reasons they developed the new guidelines. 

The first thing I notice is in Section 2 (pg7): Definitions   "A food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food."  This is updated terminology to address both IgE and Non-IgE food allergies.  Typical immediate onset allergies are IgE, that is IgE-mediated mechanisms are involved.  Non-IgE are delayed and thought to typically involve cellular mechanisms.  "The terms Allergy and Allergic Disease are broadly encompassing and include clinical conditions associated with altered immunologic reactivity that may be either IgE mediated or non-IgE mediated".

It goes on to describe terms such as Food Allergen, this addresses foods or specific ingredients and components in a food (typically proteins).  It also addresses cross-reactivity definition and significance in food allergy.  Food oils are considered low allergenicity if virtually all food proteins have been removed in processing (note low, not non-allergenicity).

I am pleased to see that there is a lot of language in this report to describe diagnosing food allergy- not limited to serum levels of IgE, but in response to tried-and-true elimination and challenge of the foods.  Things to be considered is the level of reaction, the quality of life - the balance of benefit and harm..."identification and avoidance of foods responsible for food-induced allergic reactions improve quality of life and potentially prevent life-threatening reactions and disorders.  With the appropriate evaluation, there is a low risk of erroneously diagnosing someone as food allergic and adversely affecting his or her nutritional well-being and social interactions".  

This is an important moving forward (and over due) step in the world of Food Allergy.  And as not only a mom of an FPIES child, but a Dietetic professional as well, this is of critical importance -- to properly recognize, diagnosis and treat food allergy's not only so that diets are not over restrictive but also, on the other end of the spectrum,  so that proper identification to symptoms can be made, and treated with removal of the offending food(s).   This is important because as of now, allergy's are only considered "true" if they produce an IgE and immediate immunological response.   These guidelines are helping to redefine, and hopefully reshape how adverse reactions to foods are viewed, and thus diagnosed and treated.  It is very important to be able to treat so many growing number of protein intolerant infants and toddlers, to have recognition that not all food allergies are IgE response, that Non-IgE food allergy's exist, are prevalent and a significant adverse health effect on children suffering from them.

Food Protein Induced Enterocolitis (FPIES) and Food Protein induced allergic proctocolitis (AP) are initially described on the bottom of page 8. 

A table (in section 4, pg 20) for "Diagnosis of food allergy: when should a food allergy be suspected?" and includes delayed GI reactions as well as other cutaneous, ocular, and respiratory delayed symptoms (as part of the cascade of symptoms)- it should be noted that the expert panel notes that food allergy rarely causes isolated respiratory symptoms such as asthma and allergic rhinitis.  

Included in section 4 (page 22) is an outline for Differential for Diagnosis of Food Allergy, which include addressing adverse reactions to foods that are not allergenic in origin. 

A few pages later (page 27) is the discussion on Diagnosis of non-IgE-mediated immunologic adverse reactions to food.  This is where FPIES and AP are described as Guideline for diagnosis, rationale and the balance of benefit and harms. It is a good synopsis of the research on FPIES thus far.   I am happy to see it has it's place here and described so well for the clinicians.  There are additional research articles on FPIES, and additional research is being done to further understand this diagnosis, and ultimately (hopefully) find better treatment options to provide to the families struggling with a severe protein intolerant child. 

It covers a lot of new language, encompasses newer research on Non-IgE allergies, as well as clarifications on IgE reactions.   In general, it is well written report and hopeful that with FPIES and AP being included; it will begin to be in the differential diagnosis for more kids presenting to the doctors offices with feeding intolerance's.

I suspect my child has FPIES....

I suspect my infant/child has FPIES, now what? 

FPIES is a rare illness where little is known, many doctors do not recognize it.   If you have come across information on FPIES while searching for answers to your child’s extreme reactions to food and feeding intolerances, if you have read What is FPIES here and other sources (KFA, Baby Center, Facebook)- you have found information put together by FPIES families.   What can you do now?          

1.    Start a food journal, whether breast feeding or formula.  You will also want to strongly consider stopping all foods that are not previously assured as safe.  Often reactions happen with first food introductions, so this is not as difficult to do as if/when there is a larger diet in place. Following a reaction, the gut needs time to heal; any foods that are causing even small symptoms could impede this healing process.  It is safer for your child to stop foods and continue formula or breast milk only for ~2weeks (sometimes longer, rarely shorter). 

2.    If breastfeeding, consider an elimination diet.  Eliminating the food that the child reacted to initially, and if symptoms persist (or were developing prior to full blown reaction)- you may need to consider a Total Elimination Diet where the top 8 allergens are eliminated, as well as other FPIES allergenic foods such as corn, rice, oats.  If unable to continue breast feeding, consider elemental formula (will need Rx for from MD).

3.    If formula feeding, strong considerations for hypoallergenic and elemental formula’s. 

4.   It will be important to the health of your baby that other gastrointestinal disorders and allergies with similiar symptoms of feeding intolerances are ruled out.  This can be done with a Pediatric Allergist or GI.  Other conditions include Eosinophilic Gastrointestinal disorders and Celiac Disease.

5.   You will then need confirmation of FPIES diagnosis and treatment plans.  There is no guarantee that the doctors will know what to do, or have even heard of this diagnosis.  Although awareness is being raised, so it is helpful to call ahead of time and find a doctor that is familiar with treating FPIES.  If you are not able to locate a doctor who has treated FPIES patient, find one that is willing to help by learning.  Of course we would want doctors to have protocols already in place and know exactly what to do with food trials and reactions but there is not enough known yet for protocols to be in place in most hospitals; but that does not mean the doctors can’t help.  If they want to learn, they can help. 

6.    You may want to print off articles on FPIES, as well as 2010 Guidelines for Diagnosis and Management of Food Allergy in the US and Non-IgE Food Allergy to take with to your doctor’s appointments to ask them to review for considerations for differential diagnosis if your child is having these feeding intolerances. (also see my top FPIES articles on front page).

7.  Join an online support community, such as: Baby Center, KFA, or Facebook for additional resources and support.  Families sharing experiences can be a gold-mine of information and a lifeline of support.

Managing Allergy

What a great find!  An entire book to view, and a great resource on Allergy in general! Find it here: Managing Allergy.

Chapter 10 (pg. 157) is the overview on Food Allergy.  Each chapter is divided to describe allergies in depth, all complete with their own reference section!   

On pg. 165, the discussion of FPIES.   It defines it in a table (of IgE, Non-IgE and mixed allergy) of disease manifestations, which include:"Irritability, excessive, vigorous vomiting and diarrhea a few hours after ingestion of the allergen, hypotension, lethargy, hyponatremia, acidosis, a "left-shift", and methemoglobinaemia may occur.  Stool smears may reveal blood, leukocytes or eosinophils.   A more indolent course, with failure to thrive, hypoalbuminaemia, chronic vomitting and diarrhea may occur for young infants chronically eating the allergen." 

It continues and devotes a paragraph on pg.167 for an action plan, ER treatment, resolutions of FPIES, triggers, and recommendations for challenges (.3-.6g of protein per kg of body weight to be fed in 1-2 doses...with IV inserted prior). 

I think it is a good synopsis of FPIES (especially for a book copyrighted in 1999).   I like that it gives both classic and chronic symptoms in the disease manifestations table.  Putting together more of what is known about FPIES, from research and from moms is what will help guide what should be researched next.  But if this much was known in 1999....why don't more doctors already know about it?

Fruit Protein: Another cause of FPIES

I found this article: Fruit Protein; Another cause of FPIES while reading through the previous article I posted about (New FPIES study from Isreal).  It, of course, grabbed my attention because of the commonality of so many kids in the support groups having problems with fruit proteins as much as the common triggers.   

The article describes the documented case of an infant who had a positive, classic reaction to a fruit mixture.   The confirmation was made when the fruits were stopped and symptoms subsided, and then reintroduction elicited an FPIES trigger response.

The concluding paragraph in the article is intriguing for more research, as it spells out some possible connections with fruits due to their plant tissue structures...."The present study clearly shows that also proteins contained in fruits can be responsible of FPIES, which may have a prolonged course. Plant tissues contain thousands of different proteins (5) and it is difficult to identify the culprit antigens. Common related proteins such as nonspecific lipid transfer proteins, which are resistant to proteolysis and thermal treatment, and/or pathogenesis-related proteins might be the antigens responsible for the reaction."

New study on FPIES!

Here is another great example of mom's helping mom's....another FPIES mom brought this article to my attention (thanks Ashley!) She found this article in her own researching for her son, and shared it with me.  Here is the link: The prevalence and natural course of FPIES.  It is a study done in Isreal. 

In summary, they wanted to do a research study because the prevalence and natural history for FPIES have not been determined.  The objective was to determine the prevalence, clinical manifestations, and rate of recovery for FPIES in this first large scale population based PROspective study.  They studied the feeding history of 13,019 infants!! They studied them from birth (prospective vs. retrospective as other studies have been).    The study was limited to cows milk protein induced enterocolitis (as apparently in Isreal that is predominant).  Of the 13,019 infants- 44 had confirmed FPIES.  The most common symptoms were: recurrent vomiting (100% of the patients experienced this marker for FPIES), lethargy, diarrhea, pallor, and bloody diarhea.   They also note that all patients experienced symptoms within the first 6mo.(but they were being followed for this study so this had to have helped with diagnostics); also that by 3yrs of age, 90% of the 44 had recovered from the FPIES, they did not report any reactions to soy among these 44 (or other foods) but do note that 8 (of the 44) also had IgE allergy to cows milk proteins.

The article starts out with it's references- dating back to a 1967 paper from Gryboski who studied 21 children with FPIES, and where the original description can be found.  Noting that their symptoms were vomiting, diarrhea, vomiting with diarrhea, and colic with resolution of symptoms upon removal of cows milk protein and recurrence of symptoms with reintroduction.   They note that the next big study was 20yrs later when Dr.Sicherer studied 22 patients (11 to milk, 11 to soy and 7 of those reacted to both) with the same above criteria for delayed vomiting, diarrhea, resolution of symptoms with removal of proteins and recurrence with reintroduction.  It goes on to report how studies have shown that there are some lab reports that may indicate positive correlation with FPIES but are not necessary; such as increased neutrophils in the blood counts 5-8hrs after ingestion and that the mechanisms are not clearly understood but have found involvement with Tumor Necrosis Factor-alpha (TNF-a) increase response and a decrease in Transforming Growth Factor-beta (TGF-b) may be an important role in understanding the mechanisms for diagnosis.  In covers that other studies have shown that FPIES can be triggered by other food proteins and common ones include: rice,oats,barley,peas,sweet potato,chicken and turkey.   They also go on to say that the largest report to date was on 35 children and that milk protein is actually the 3rd most common offender. 

Something I find very interesting to find in print, in an FPIES study, is something so many moms have observed as "classic" ways of determining if symptoms are FPIES trigger while trialing a new food....stop the trial, rest, and restart, if symptoms return stronger- consider it a fail, is something so many moms have connected- on our own.   This study puts it into print...."A distinguishing feature of FPIES is that reintroduction of the offending food, either inadvertently or by an oral food challenge, leads to characteristic symptoms delayed approx.2hrs after the ingestion of the offending food". 

The article clarifies that this study is the first largest population based study on FPIES (to cows milk protein).   The criteria used for their cows milk protein induced FPIES diagnosis was:

• less than 9mo. of age at onset of symptoms
• GI symptoms: repetitive vomiting, diarrhea, or both within 24hrs.
• absence of IgE sources
• resolution of symptoms with removal of cows milk proteins
• positive symptoms with re-challenge

Oral challenges were performed for diagnosis (a few families refused the oral challenge due to severe initial reactions to cows milk); protocol for the challenge was written using infant formula and time/dosed starting at 5ml, wait 10min, then 20ml, wait 20min, then 30ml, wait 20min, then 60ml, wait 45min, then 120ml, wait 45min, then 150ml and wait 3hrs.  Total a little over 5hrs to ingest 385ml (which is almost 13oz.); they then waited and observed an additional 3hrs; and also had a 2 week follow up (for delayed reactions). 

The study statisical analysis on their population including: infant sex, gestational week, birth weight, maternal age, type of delivery, number of siblings, dairy product consumption of mother, and religion (Jewish or non-Jewish), and finally age of when cows milk proteins were introduced.    The study found the correlation with FPIES to be with type of delivery and religion of the parents. 

It goes on to discuss that of the population base of 13,019 infants, 44 were given the diagnosis of FPIES based on classic criteria:

• recurrent vomiting
• lethargy
• diarrhea
• pallor
• bloody diarrhea

This paragraph describes how some of the infants experienced build reactions- after multiple exposures- another piece many moms note (and a piece that makes getting the diagnosis difficult for some children), this study showed that some infants tolerated the cows milk formula for more than 4-5days and even up to 14-30days before development of classic symptoms.   Of note, this study had no patients with FPIES to other foods.  Interesting,wonder if it is specific to this country?

There was also discussion about the oral challenge and how not every infant reacted on the first dose, stating most infants tolerated up to 121ml or more without symptoms but all experienced symptoms by the 2hr time frame (not sure what this showed because with delayed reactions such as this you would have to stop at 5ml and wait 2hrs for symptoms to see if 5ml was indeed enough to elicit a reaction response.  They did note this also, in their discussion points of the article: "Because all doses were given within 4 hours or less, it is not possible to know which dose was responsible for the reaction. An optimal study design would be to administer a single dose and increase it every 2 or more days."   The other interesting finding to note was that all the infants who participated in the oral food challenge recovered on oral re hydrating drinks and close monitoring- none required an IV (although, again note that a few parents refused the oral challenge due to such severe reaction on first exposures).  

The study also addressed "rate of recovery"...ie, when did they outgrown it?  Reporting that 50% of the patients had outgrown it by 1yr, 75% by 18mo., and 88.9% by 2yrs.; with only 2 patients still remaining positive for symptoms by 42mo.  Of very interesting note is that "among the patients undergoing an oral food challenge, there was a tendency for them to have a later recovery age compared with those for whom the parents refused a challenge".   Which I interpret to mean, without strict avoidance; there is greater chance of sensitizing the cell mediators memory which leads to longer time for outgrowing.   Strict avoidance is necessary.  

In discussion points, a few points of interest for further study is the criteria for diagnosis (involvement of diarrhea, as found that diarrhea is not always present and appears to more of a result of chronically exposed children). And, as mentioned above, the study was inconclusive for the amount of milk that could induce the reaction.  Interesting to note that, with this population base, C-section delivery and religion were noted as risk factors although unclear why.  

Of note, they noted that Dr.Sicherer's study has been conducted on FPIES in solid foods, where none of the infants in this study developed FPIES to solid foods.  They reviewed Dr.Sicherer's study to find that only 7 of the patients he studied had FPIES to solid foods and considered this a "more severe and unique subgroup of FPIES".  Also noted that none of the infants in this study required IV placement for their oral food challenges and the study questions if this is necessary as per protocols in hospital now. 

They summarized with a statement I agree completely on: "....the prevalence of FPIES is relatively high, and thus pediatricians should be aware of this condition to avoid unnecessary hospitalizations and over treatment".  And I would add to that avoiding under-treatment as well.  

Treatment Plans

FPIES protocols do not yet exsit. Doctors are too unfamiliar with the multiple mechanisms for this illness. Allergists treat it under IgE protocols, which primarily work, especially when you think of this Non-IgE allergy as an anaphyalaxis of the gut. GI's treat it under EoE protocols, which are helpful and resourceful- especially in the beginning stages when the treatment is to remove all foods, give the gut rest and find a baseline, and then trial foods. Ideally, FPIES needs to be a multi-disciplinary approach driven protocols that are individualized to the specific needs of the child.

The goal of treatments plans should be to develop oral tolerances and control inflammatory responses, while managing gut dysbiosis to achieve homeostasis.

To understand FPIES, it is helpful to understand where current thinking of the root mechanisms are, which are multi-factorial:

• Genetics- immune responses (via cytokines) driven my genetic markers
• Environmental influences- how the immune system is influenced by the digestive tract (birth environment, breast milk, formula, antibiotics,etc...)
• Gut Micro flora - digestion (GALT) and gut homeostasis can influence the degree and severity of the protein intolerance's (increased intestinal permeability- or also referred to as leaky gut).  
• Other factors still to be determined (more research needed).

Understanding Oral Tolerance (immune responses):  

Food consumed enters the body, begins the immunological process, involving white blood cells (WBC's) called Leukocytes and the chemicals they produce, called Cytokines. When the food causes an immune response, it is an antigen. That antigen activates the lymphocytes. Lymphocytes are the first to recognize and respond to foreign substances in the body. Lymphocytes are B cells or T cells. Tcells (commonly referred to as the gatekeepers of the immune system) assign T helper cells (Th) to release messaging cytokines (Cytokines are were the messaging may be part of the dysfunction in FPIES- where the immune system meets the genetics...more on this in an upcoming posts).

 Thelper cells are divided into 3 main category's for molecule recognition:

 Th1- response when anything foreign enters the body, releases cytokines (messengers) to inflammatory markers, Tumor Necrosis Factor-alpha (TNF-a).  Necrosis= death, inflammation can be a protective measure involving cell death of the invading molecule- but it needs regulating (or you have auto-immune disorder of the body attacking itself); which is where Transforming Growth Factor (TGF-B1) comes in as it is anti-inflammatory cytokine that is a regulator to balance of inflammation in immune responses. There are other cytokines involved, but this is the level at where research has been, more research is needed to study the role of further cytokines, and the impact genetics, environment and gut flora play in this mechanism.   IgG antibodies will be present from this response, although IgG testing remains inconclusive to diagnosis FPIES trigger responses as these antibodies will be raised in any Th1 response (viral, immunization,etc) but may be part of a diagnostic tool in the future as it already is with gluten intolerance and Celiac disease. Th1 is designed to protect the body from virus, pathogens, tumor cells (to attack and rid them in the body); but an immature immune system is susceptible to producing Th1 responses to food proteins as well. Why some childrens' immune systems are immature at a time when they should be matured (breast milk, formula, first foods) is not yet fully understood and may involve genetics, environment factors, or both.

Th2- IgE antibodies are produced in response to antigens. Some FPIES kids can have co-existing IgE (Th2) and Non-IgE (Th1) responses.

Th3 - oral tolerance, the body recognizes food proteins as safe and nourishment to cells and does not initiate an immune response.

Understanding Inflammatory Responses:

Food is broken down into molecules, molecules are picked up by the cells in the gut (via the lymphoids- GALT) where antigenic proteins are presented to T cells (as described above). Food molecules couple with the Tcells and travel through the lymph system to the Thymus gland, where the regulatory (Treg)cells can stop any attack by the process carried out by the Cytokines (messengers). In FPIES, the cytokines involved are thought to be Transforming Growth Factor- beta (TGF-b) and possibly interleukin such as IL-10. TGF-b is an anti-inflammatory mediator (promotes oral tolerance- as stated above, the cytokine responsible for not allowing inflammation, or cell death). So, Treg cells regulate the initial response by sending out correct messengers (cytokines- TGF-b, IL-10, IL-17...).   It is understood that this process is dysfunctional in FPIES, the degree of it's function/dysfunction may be what differientes the chronic vs. classic and and the severe cases of FPIES.   Again, further research is needed to identify the mechanisms involved at this cytokine level and what is influencing the dysfunction.

Understanding Digestion and Gut Microflora:
Intestinal flora forms a natural barrier to pathogens and also work together with the GALT (intestinal immune system within the GI tract made of lymphoid cells), Food allergic response in the gut activated by the immune system (via the GALT), is thought to lead to increased intestinal permeability, which can lead to further intolerance's and dysbiosis. One of the roles of gut micro flora is to help regulate the immune system.  Disturption of microflora disrupts Treg responses (which regulates the cytokine responses- which regulates inflammation or anti-inflammatory mediators).   When the antigenic presenting dendritic cell (where micro flora have their role) activates the lymphocytes, it leaves the mucousa via the lymph and enters the blood stream via the thoracic duct. The activated lymphocytes then travel back to the gut and can colonize in the same mucousa or other mucousal sites along the GI tract. This is where the Tmemory cells are then stored and activated upon re-exposure to trigger (antigen) proteins (and likely why the re-exposure can be a more intense response because of the recognition from previous activated lymphocytes.  Probiotics can help manage the gut homeostasis and further reduce the mechanism of allergy responses and restore the natural barrier.

FPIES research

Active research at Mt.Sinai: Clinical trials

Shock Symptoms & ER letter

The research articles report 20% of FPIES kids experience full shock. 

Shock is very serious, and any symptoms of reactions should be discussed and outlined with your child's doctor.  

Shock in FPIES kids can be obvious but there are also symptoms of late-shock that can be confusing but remain very serious and concerning.   It is beneficial for your child to have an ER letter (click here for sample) for treatments, that outlines the need for IV hydration and montioring following a reaction.  

I found this article on Pediatic Shock to be very educational.  I, personally, have had to learn from my son's reactions as I didnt' recognize his body going into shock, because he hasn't gone into immediate shock but does go into late-shock.

The shock and dehydration is not necessarily proportionate to the volume depleted (my son took in 70oz. the days following a vomiting reaction and he still had dehyration when checked 3days later!).   Every child is different and all reactions should be taken seriously, and assessed carefully.

This is another area where more research would benefit.   The dehydration and shock can come from the capilary leakage that happens from the inflammatory response actions.   For further reading::  Complement activation in relation to capillary leakage in Children with septic shock and purpura.    It does not address FPIES specifically but sheds some light on the activations of the inflammatory process.

My doctors are unfamiliar with FPIES, now what?

If you suspect your child has FPIES, a consult to a Pediatric Allergist or Pediatric Gastroenterologist is warrented.   A workup to rule out other medical conditions that may mimic FPIES symptoms in infants may be performed.   If you have been referred to these subspecialists and they still are unsure of FPIES, or have never treated it.  It may be helpful to take FPIES research articles with and keep these things in mind about treatment protocols. 

Articles that may be helpful: 

1. 2010 Guidelines for Diagnosis and Management of Food Allergy in the US
2. FPIES- a Review
3. FPIES Pediatrics 2003 Journal Article
4. FPIES 2009 Journal (abstract)

FPIES protocols do not yet exsit. Doctors are too unfamiliar with the multiple mechanisms for this illness. Allergists treat it under IgE protocols, which primarily work, especially when you think of this Non-IgE allergy as an anaphyalaxis of the gut. GI's treat it under EoE protocols, which are helpful and resourceful- especially in the beginning stages when the treatment is to remove all foods, give the gut rest and find a baseline, and then trial foods. Ideally, FPIES needs to be a multi-disciplinary approach driven protocols that are individualized to the specific needs of the child.

The goal of treatments plans should be to develop oral tolerances and control inflammatory responses, while managing gut dysbiosis to achieve homeostasis.

To understand FPIES, it is helpful to understand where current thinking of the root mechanisms are, which are multi-factorial:

• Genetics- immune responses (via cytokines) driven my genetic markers
• Environmental influences- how the immune system is influenced by the digestive tract (birth environment, breast milk, formula, antibiotics,etc...)
• Gut Micro flora - digestion (GALT) and gut homeostasis can influence the degree and severity of the protein intolerance's (increased intestinal permeability- or also referred to as leaky gut).  
• Other factors still to be determined (more research needed).

Understanding Oral Tolerance (immune responses):  

Food consumed enters the body, begins the immunological process, involving white blood cells (WBC's) called Leukocytes and the chemicals they produce, called Cytokines. When the food causes an immune response, it is an antigen. That antigen activates the lymphocytes. Lymphocytes are the first to recognize and respond to foreign substances in the body. Lymphocytes are B cells or T cells. Tcells (commonly referred to as the gatekeepers of the immune system) assign T helper cells (Th) to release messaging cytokines (Cytokines are were the messaging may be part of the dysfunction in FPIES- where the immune system meets the genetics...more on this in an upcoming posts).

 Thelper cells are divided into 3 main category's for molecule recognition:

 Th1- response when anything foreign enters the body, releases cytokines (messengers) to inflammatory markers, Tumor Necrosis Factor-alpha (TNF-a).  Necrosis= death, inflammation can be a protective measure involving cell death of the invading molecule- but it needs regulating (or you have auto-immune disorder of the body attacking itself); which is where Transforming Growth Factor (TGF-B1) comes in as it is anti-inflammatory cytokine that is a regulator to balance of inflammation in immune responses. There are other cytokines involved, but this is the level at where research has been, more research is needed to study the role of further cytokines, and the impact genetics, environment and gut flora play in this mechanism.   IgG antibodies will be present from this response, although IgG testing remains inconclusive to diagnosis FPIES trigger responses as these antibodies will be raised in any Th1 response (viral, immunization,etc) but may be part of a diagnostic tool in the future as it already is with gluten intolerance and Celiac disease. Th1 is designed to protect the body from virus, pathogens, tumor cells (to attack and rid them in the body); but an immature immune system is susceptible to producing Th1 responses to food proteins as well. Why some childrens' immune systems are immature at a time when they should be matured (breast milk, formula, first foods) is not yet fully understood and may involve genetics, environment factors, or both.

Th2- IgE antibodies are produced in response to antigens. Some FPIES kids can have co-existing IgE (Th2) and Non-IgE (Th1) responses.

Th3 - oral tolerance, the body recognizes food proteins as safe and nourishment to cells and does not initiate an immune response.

Understanding Inflammatory Responses:

Food is broken down into molecules, molecules are picked up by the cells in the gut (via the lymphoids- GALT) where antigenic proteins are presented to T cells (as described above). Food molecules couple with the Tcells and travel through the lymph system to the Thymus gland, where the regulatory (Treg)cells can stop any attack by the process carried out by the Cytokines (messengers). In FPIES, the cytokines involved are thought to be Transforming Growth Factor- beta (TGF-b) and possibly interleukin such as IL-10. TGF-b is an anti-inflammatory mediator (promotes oral tolerance- as stated above, the cytokine responsible for not allowing inflammation, or cell death). So, Treg cells regulate the initial response by sending out correct messengers (cytokines- TGF-b, IL-10, IL-17...).   It is understood that this process is dysfunctional in FPIES, the degree of it's function/dysfunction may be what differientes the chronic vs. classic and and the severe cases of FPIES.   Again, further research is needed to identify the mechanisms involved at this cytokine level and what is influencing the dysfunction.

Understanding Digestion and Gut Microflora:
Intestinal flora forms a natural barrier to pathogens and also work together with the GALT (intestinal immune system within the GI tract made of lymphoid cells), Food allergic response in the gut activated by the immune system (via the GALT), is thought to lead to increased intestinal permeability, which can lead to further intolerance's and dysbiosis. One of the roles of gut micro flora is to help regulate the immune system.  Disturption of microflora disrupts Treg responses (which regulates the cytokine responses- which regulates inflammation or anti-inflammatory mediators).   When the antigenic presenting dendritic cell (where micro flora have their role) activates the lymphocytes, it leaves the mucousa via the lymph and enters the blood stream via the thoracic duct. The activated lymphocytes then travel back to the gut and can colonize in the same mucousa or other mucousal sites along the GI tract. This is where the Tmemory cells are then stored and activated upon re-exposure to trigger (antigen) proteins (and likely why the re-exposure can be a more intense response because of the recognition from previous activated lymphocytes.  Probiotics can help manage the gut homeostasis and further reduce the mechanism of allergy responses and restore the natural barrier.

Tests and Labs

NOTE: This post is under construction


Tests that may be done FPIES is suspected:

Upper Endoscopy

Colonoscopy/Sigmoidoscopy

Gastric Emptying Study

Motility study

X-ray

Upper GI study

IgE (RAST or SPT)

Stool studies

CBC

Tests that may help with identifying food sensitivies:

Atopy Patch Testing

IgE Allergy vs. Non-IgE Allergy

IgE FOOD ALLERGY: (Typical food allergy) Immediate onset reactions	Non- IgE Food Allergy: (PROTEIN INTOLERANCE) Delayed onset reactions
The body's abnormal immune response to a food, usually a protein.	Mediated by non-IgE antibodies and/or cellular immune responses.
Common Conditions*: 1.     IgE food allergy (ie egg, milk, peanut, tree nut, soy, wheat, shell fish…) 2.     Eosinophilic Disorders 3.     Oral Allergy Syndrome *list is not inclusive, please see your doctor for any symptoms/diagnosis	Common conditions*: 1.     Milk/Soy Protein Intolerance 2.     Multiple Food Protein Intolerance 3.     Food protein-Induced Allergic Protocolitis 4.     Food Protein Induced Enterocolitis Syndrome 5.     Food Protein Enteropathy 6.     Celiac Disease (also auto-immune) 7.     Eosinophilic Disorders (also IgE) *list is not inclusive, please see your doctor for any symptoms/diagnosis
Common Respiratory Symptoms: ·          Sneezing, runny nose, congestion, hay fever ·          Shortness of breath ·          Throat swelling ·          Cough ·          Allergic asthma ·          Pink eye/eye swelling	Common Respiratory Symptoms: ·          Non-allergic sneezing, congestion, runny nose ·          Non-atopic cough, asthma ·          Recurrent or chronic sinus inflammation/infections ·          Reflux disease ·          Recurrent ear infections ·          Eye swelling ·          Enlarged adenoids
COMMON GI SYMPTOMS: Nausea/Vomiting/Diarrhea Cramping abdominal pain Reflux/Difficulty swallowing Swelling (tongue,lips,face) Itching/swelling of the tongue, lips, mouth Dizziness Fainting Severe reactions (anaphylaxis) can be life threatening and require immediate medical attention and can include: Itching or tightness in the throat Difficulty breathing Wheezing/coughing Rapid heart rate Low blood pressure Loss of consciousness Symptoms usually occur within minutes to 1-2 hours after ingesting the food.	COMMON GI SYMPTOMS for MSPI/MFPI: Mucus/Blood in Stools Inconsolable and Extended Crying/Colic Disrupted Sleep Malabsorption/Vitamin Deficiency "Spit-up" an hour+ after feeding Sulfur/sour smelling stools Diarrhea and/or constipation Red ring around the anus Peeling diaper rash Gas/wind Mouth itching Dysbiosis Symptoms can occur hours to days after ingesting the food. COMMON SYMPTOMS for FPIES will include above and: Loss of appetite Violent/forceful/projectile vomiting Lethargy Dehydration Low body temp or fever Low blood pressure Shock Click here for more information on: Celiac, Eosinophilic disorders
Common skin symptoms: ·          Eczema ·          Hives ·          Rashes (dermatitis)	Common skin symptoms: ·          Eczema ·          Rashes/flushing ·          Itchy skin ·          Diaper rash.
Diagnostic Tests: ·          RAST (serum IgE) ·          Skin Prick Testing ·          EE requires endoscopy	Diagnostic Tests: ·          Atopy Patch Testing ·          Food elimination and challenge ·          Endoscopy/colonoscopy ·          Medical history

References:

Non-IgE food Allergy by Dr.Jyonouchi http://www.pcrcd.org/Jyonouchi_IA-DT.pdf 

2010 Guidelines for Diagnosis and Management of Food Allergy in the United States  http://www.niaid.nih.gov/topics/foodallergy/clinical/Pages/default.aspx

Protein Intolerances  http://emedicine.medscape.com/article/931548-overview