Non-IgE Food Allergy

A Food allergy is defined, as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a the food (antigen) that are either IgE or Non-IgE mediated.  Food Allergy is now being increasingly recognized as classified, IgE and/or Non-IgE mediated. 

 

IgE stands for Immunoglobin E, a measurable antibody producing immune response to a food protein.  Symptoms are immediate onset (0-2hrs within ingestion) and can include, but not limited to: hives, sneezing, wheezing, itching, red eyes, throat swelling, allergic asthma, and severe reactions can include rapid heart rate, low blood pressure, anaphylaxis (see table below).   The most common ("top 8") food allergens include: eggs, milk, peanut, tree nut, wheat, shellfish, and soy but are not limited to these foods,  any food with a protein can elicit an allergic reaction.  Also included in the immediate immune response is Oral Allergy Syndrome (OAS) and some components of Eosinophilic disorders (EGID).

A Non-IgE Allergy is cell-mediated (vs.antibody) and defined by a delayed response of the immune system, typically involving the gut.  No measurable antibodies are produced, symptoms are delayed (2+hours from ingestion) and include, but not limited to: sneezing, itching, runny nose, asthma, reflux, colic, abdominal pain, nausea, vomiting and diarrhea, and severe reactions can include lethargy, hypotension, and shock (see table below).  Like IgE allergies, the "Top 8" are included but are not limited in Non-IgE food allergies as any food protein can elicit this response.  Diagnosis included in this immune response are: Milk/Soy Protein intolerance, Multiple Food Protein Intolerance, Food Protein-Induced Allergic Colitis, Food Protein-Induced Allergic Procolitis, Food-Protein Induced Enterocolits, Food Protein Enteropathy, Celiac Disease, and Eosinophilic Disorders.  

IgE FOOD ALLERGY: (Typical food allergy) Immediate onset reactions	Non- IgE Food Allergy: (PROTEIN INTOLERANCE) Delayed onset reactions
Mediated by production of Immunoblogin E antibodies in response to a food, usually a protein.	Mediated by non-IgE antibodies and/or cellular immune responses to a food-protein.
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.     Food Protein-Induced Allergic Colitis 3.     Food protein-Induced Allergic Protocolitis 4.     Food Protein -Induced Enterocolitis Syndrome 5.     Food Protein-Induced Enteropathy 6.     Celiac Disease (also auto-immune) 7.     Eosinophilic Disorders (also IgE) M     Milk/Soy Protein Intolerance 2.     Multiple Food Protein Intolerances *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-allergic 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: Mucus/Blood in Stools Inconsolable and extended crying/”colic” Loss of appetite Food aversions Disrupted Sleep Malabsorption/Vitamin Deficiency "Spit-up" an hour+ after feeding Sulfur/sour smelling stools Diarrhea and/or constipation Red  "ring" on bottom/peri-anal severe/persistent diaper rash Gas Mouth itching Intestinal dysbiosis Weight loss/difficulty gaining Symptoms can occur hours to days after ingesting the food. Severe reaction (FPIES) can be life threatening and require immediate medical attention and can include: Violent/forceful/projectile vomiting Lethargy Diarrhea 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             Dermatitis
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:

1. Guidelines for Diagnosis and Management of Food Allergy in the United States (2010)
2. Medical Journal Article on Protein Intolerance (April 2010)
3. Nonimmunoglobin E-Mediated Immune Reactions to Foods by Dr.Spergel (2006)
4. Non-Ige Food Allergy by Dr.Jyonouchi (2008)
5. Food Allergy: Review, Classification and Diagnosis by Dr.Spergel & Dr.Cianferoni (2009)
6. Food protein-induced proctitis/colitis, enteropathy, and enterocolitis of infancy by Up To Date (2011)

Non-IgE Food Allergy is on the rise, and increasing in awareness as a seperate and valid clinical entity of food allergy, over the past 5-10years.   Although still little medical research and reports exist on this allergy subset.  Information can be found in the above resources, as outlined below:

As stated in the 2010 Guidelines for Diagnosis and Management of Food Allergy in the United States , "There is no current treatment for Food Allergy, the disease can only be managed by allergen avoidance or treatment of symptoms.   Moreover, the diagnosis of Food Allergy may be problematic, given that nonallergic food reactions, such as food intolerance [sugar,chemical,pharmacological], are frequently confused with Food Allergy's".  

This is a comprehensive report from an expert panel and includes:

• Definitions of Non-IgE food allergys, with symptoms and a table of Immediate and Delayed symptoms with their target organs affected (table IV on page 21).
• Diagnosis of Non-IgE mediated immunologic adverse reactions to food (section 4.3, page 27)
• Eosinophilic GI diseases
• Food protein induced enterocolitis
• Food protein induced allergic proctocolitis
• Food protein induced enteropathy syndrome
• Allergic contact dermatitis
• Systemic contact dermatitis
• Heiner syndrome. 

The Medical Journal Article on Protein Intolerance article (last updated April 2010) provides a full overview of the many manifestation of protein intolerance's. Discussions of IgE and Non-IgE Protein intolerance with a focus on GI symptoms being the most common in children with reactivity to food proteins.

The article outlines a basic discussion on oral tolerance and the immunologic and inflammatory mechanisms related to this process.   "Under normal circumstances, food antigen exposure via the GI tract results in a local immunoglobin A (IgA) response and in activation of suppressor CD8+ lymphocytes that reside in the gut-associated lymphoid tissue (Oral tolerance).  In some children who are genetically susceptible, or for other as-of-yet unknown reasons, oral tolerance does not develop and different immunologic and inflammatory mechanisms can be elicited".

Other points of interest:

• Food protein intolerance's can be IgE or Non-IgE mediated, studies have shown the role of gut T cell lymphocytes in the development of GI food allergy. 
• Mention here of IgG antibodies, but that their role is still not clear.  
• Protein Intolerance's generally resolve by age 5, with the maturing of the mucosal immune system. 
• A table is included to classify adverse reactions to foods. 
• With food protein intolerance's, GI symptoms are most commonly presented and can include:
• Oral Allergy Syndrome (IgE)
• Immediate GI hypersensitivy (IgE)
• Eosinophilic esophagitis, Eosinophilic gastrities, Eosinophilic gastroenteritis (IgE and Non-IgE)
• Food Protein Induced Enterocolitis
• Food-induced enteropathy
• Gluten-sensitive enteropathy
• Protein-losing enteropathy
• Food-Induced Proctocolitis
• Food-Allergy induced gastroesophageal reflux (GERD)
• Chronic constipation
• Colic
• Allergic dysmotility
• Multiple Food protein intolerance of infancy
• Dermatologic symptoms
• Respiratory symptoms
• General and non-specific symptoms are also recognized.  

A Review article on Nonimmunoglobin E-Mediated Immune Reactions to Foods by Dr.Jonathan Spergel (from 2006) discusses an overview of Non-IgE Food allergy that includes a table for differential diagnosis, with detailed discussions on:

• Skin reactions (Dermatitis herpetiformis and atopic dermatitis)
• Gastroinestinal Disorders (FPIES, Celiac)
• Combined IgE and T-cell mediated GI disorders (Eosinophilic)
• Non-IgE-Mediated Respiratory Reactions (Food-Induced Pulmonary Hemosiderosis)
• Clincal Tests for Non-IgE-Mediated Reactions
• Oral Food Challenges

In 2009, Dr. Jonathan Spergel with Dr. Antonella Cianferoni wrote Food Allergy: Review, Classification and Diagnosis outlines the increased recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein induced enterocolitis.  The document also includes an easy to read chart for the classification of adverse reactions to foods. 

Manifestations of Food Allergy: Evaluation and Management was written by Dr.Scott Sicherer and reviewed by Dr.Hugh Sampson (in 1999) and includes tables that provide the differentiation of Food Intolerance's (Non-immunologic adverse reactions to food) and Food Allergy (IgE and Non-IgE and their target organs and disorders.   Dr.Sicherer also provides a sample Emergency Health Care Plan for children with allergies. 

In the article Non-IgE Mediated Food Allergy by Dr.Harumi Jyonouchi, the gut mucosal barrier and it's involvement in Non-IgE food allergy is thoroughly reviewed.   "The gut mucosal barrier is thought to have developed to execute an immensely difficult task; digestion and absorption of nutrients without provoking immune responses and cohabiting with commensal flora in a mutual beneficial relationship while maintaining an immune defense against pathogenic microbes".  Her review discusses, with immunological details:

• Intestinal Mucousal Immune System-discusses components of the mucosal immune system associated with the development of food allergy.
• Intestinal Homeostasis - Tolerance Induction and Maintenance- discusses mechanisms of tolerance induction and immune homeostasis.
• Factors Affecting Intestinal Immune Homeostasis- discusses genetic and environmental factors
• Non-IgE Food Allergy- discussed the pathogenesis of Non-IgE food allergy and clinical and laboratory findings.
• Diagnosis and Treatment- discussed importance of elimination diet and the importance of developing reliable laboratory testings for diagnosis of Non-IgE food allergy.  

Dr.Jyonouchi concludes to say that Non-IgE food allergy is "an easily treatable clinical entity. However when under-diagnosed/under-treated, serious and possibly irreversible complications can occur."

These delayed non-IgE cell-mediated food allergic responses are increasing in numbers.  More, and continued, research into the pathophysiology of the mechanisms of Non-IgE food allergy spectrum is needed, as well as awareness of clinical symptoms for timely diagnosis and treatment.