This young lady’s mother had with her an article that escaped my attention. The article was written by known experts in the field of Allergy (the lead author was Anna Nowak-Wegrzyn with Hugh Sampson, Robert Wood, and Scott Sicherer as contributing authors). The paper was a nice review of FPIES and a study of 14 special children. I think that any allergist who sees young children should review this paper. These young children can present with signs that are possibly consistent with anaphylaxis.

 The article was published in the journal Pediatrics in 2003. It is a review of 14 children who presented over a five year period at the Mount Sinai Pediatric Allergy and Immunology Clinic (New York, NY) and to the Allergy Clinic at Johns Hopkins Children’s Center (Baltimore, MD). The reactions that these children experience include severe diarrhea and vomiting which can lead to dehydration and shock. This is a clinical diagnosis; there are no specific laboratory tests that make the diagnosis. A food challenge can confirm the diagnosis.

Milk and soy have been the most commonly implicated foods causing FPIES. This article shows that other foods specifically solid foods have been shown to be associated with this syndrome; rice, oat, barley, peas, string beans, squash, sweet potato, chicken, and turkey. These children underwent food challenges to show the cause-effect relationship between the exposure and the symptoms. There were many combinations of foods causing the problem; cow’s milk alone, soy milk alone, both cow and soy milk, a single solid food, and more than one grain. The group was compared to children who were only milk/soy sensitive.

                The profile of the Solid Food FPIES population was as follows;

• Age at onset of the reaction:    5.5 months (range 3-7 months)
• Age at resolution:                      24 months (range 14-44 months)

                The Milk/Soy FPIES profile was the following;

• Age at onset of the reaction:   1.0 months (range 2 days to 12 months)
• Age at resolution:                      28 months (range 14-21 y)

This was the first published study of FPIES triggered by solid food. Oat was the most common food causing solid-food FPIES. The study also showed that breast-feeding may have a protective role in preventing/delaying the development of FPIES. The diagnosis of solid-food FPIES was not made until after two reactions. It was also noted that these reactions were severe. The delay in diagnosis was attributed to a number of possible factors; low incidence of the disorder, a presentation that looks like septic shock, and the belief that solid foods such as grains, vegetables, and poultry are of low allergenic potential. It was also noted that the time course of the reaction may delay making the correct diagnosis. The daily feeding of milk – cows and soy, leads to chronic problems. The re-introduction of the milk causes symptoms two hours after the exposure.  As mentioned previously another problem is the lack of any test (other than avoidance and a food challenge) to confirm the diagnosis.

Another point that was made was that almost half of the children in this series had multiple food sensitivities. Children who were already on a casein hydrolysate formula had a median of four solid-foods that they were sensitive to.

No infant developed FPIES with exclusive breast feeding in this series.  The authors pointed out that they were unaware of any reports of FPIES during breast feeding with absolutely no direct oral feeding of an offending food. No infant developed FPIES to milk/soy after age 1 years and the oldest child who had the solid-food FPIES was 7 months old. There were no ‘predictors’ of which child with milk/soy FPIES would go on to develop solid-food FPIES.

The Bottom Line-

The reaction of vomiting/diarrhea possibly leading to shock can be consistent with an IgE-mediated reaction and these are perhaps more common than FPIES. Such a reaction would lead to an allergy evaluation which will be negative if the diagnosis is FPIES. However, the infant is still at risk for a severe reaction with re-exposure.

Board certified allergists are credentialed in the care of allergic conditions in both pediatrics and internal medicine. Some of us went into allergy after completing training in pediatrics and others were trained in internal medicine. FPIES would not have been a clinical entity seen during internal medicine training. It may have been seen/talked about for a pediatric oriented allergist. FPIES favors infants. My point to all this is that although very rare, we need to keep this type of presentation in mind when seeing young infants with scary episodes of vomiting leading to shock with solid-food exposure. Their evaluation will show no evidence of allergic sensitization. We can help by teasing out the history of exposures and clinical course. We can offer recommendations for avoidance of the common foods that have triggered solid food-induced FPIES. This profile of young infants reacting in such a violent way needs to be considered in the evaluation especially if they have had issues with cow’s milk or soy milk.

This young lady made an impression on me. Her story was very scary. She caused me to go back to the literature and review what is known about her presentation.

Fred Leickly

Key Points

•  Food allergies can be classified as IgE-mediated, non-IgE-mediated, or mixed.
•  The diagnosis is made from a complete history and performing directed testing.
•  Despite new developments in treatment, for now it is only avoidance.

Purpose of the article

               The purpose of this article is to review the current state of knowledge regarding the mechanisms, the diagnosis, and the treatment of food allergy and eosinophilic esophagitis.

Background

               Food allergy affects 6-8% of children and 3-4% of adults. The prevalence of food allergy is increasing.

               Any food can cause a reaction. There are a few foods that account for most reactions; cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

               Most food allergy presents in the first few years of life.

               Almost 80% of children resolve allergies to milk, egg, wheat, and soy. Far fewer resolve tree nut allergy (about 9%) and peanut allergy (20%). Allergies to fish and shell fish tend to persist into the adult years.

               A major risk factor for the development of food allergy is a family history of allergy. The presence of allergy in the parents, not extended family member is the risk factor.

Becoming allergic or tolerant

               Food allergy may be more prevalent in children due to; an immature gut barrier, low IgA levels in the gut, lower stomach acid levels (high pH), and low levels of digestive enzymes. There are also immune mechanisms in play that suppress an immune response that can lead to developing a food allergy. Normally, the immune system works to achieve food tolerance. Alterations to the immune system checks this drive towards tolerance and can lead to sensitization and food allergy.

Factors that contribute to food allergy

• The dose of the food
• The structure of the food
• Processing of the food
• The route of the initial exposure
• The gut flora (bacteria in the gut)
• The acidity of the stomach
• Genes

High doses and low doses of food can lead to tolerance (no allergy), but how this happens varies to the food. Food allergens that are soluble (dissolve) are less sensitizing.  Dry-roasted peanuts are more allergenic than raw or boiled peanuts (less soluble).

Gut flora refers to bacteria in the gastrointestinal system. Current research with germ-free mice suggests that they are prone to develop more food allergy or fail to develop food tolerance. The use of antibiotics in these germ free mice leads to the development of sensitization to food and subsequent food allergy. The acidity of the gut may be too high not allowing for proper digestion of food. The use of antacids increases the risk of developing food allergy.

Types of Immune Responses to Food

• Metabolic- lactose intolerance
• Pharmacologic- chemicals/contaminants
• Bacterial- food poisoning
• Psychological- food aversion
• Immunologic- allergy (IgE, non-IgE, mixed)

The Diagnosis of IgE-mediated Food Allergy

               The most important aspect in making the diagnosis is the history- NOT THE LABORATORY RESULT!

               Food allergy is not subtle. The appropriate questioning will tease out the exposures.

• What are the potential food culprits?
• How much was eaten?
• What was the timing between exposure and symptoms?
• What were the symptoms- are they consistent with an IgE-mediated reaction?
• Any related factors- exercise, alcohol, medication use

               The symptoms of an IgE-mediated reaction (predictable by allergy testing) will generally occur soon after the exposure, but may be delayed for a few hours.

               The symptoms of a non-IgE-mediated reaction will occur several hours to days later.

               The ‘gold standard’ for the diagnosis of a food allergy is the double-blind, placebo-controlled food challenge.

Allergy Testing- Commercially available skin prick tests are a rapid and sensitive way to screen for food allergy. Negative allergy skin prick tests have more than a 95% negative predictive value- when I show that the skin test is negative to a food, I have a 95% chance of being correct and 5% chance of being wrong with this study.

               The positive test indicates the presence of IgE antibody against the food and SUGGESTS a clinical food allergy.  The specificity of the test is 50% making a positive result more difficult to interpret than the negative skin test result. This is why we need to be careful in selecting allergy tests.

               The size of the skin test response does not necessarily correlate with the potential severity of a reaction- You cannot say a child is very allergic based on the size of their test. You can say that they make a significant amount of antibody.

Allergy Testing- Immunoassays

               DO NOT USE THE WORD ‘RAST’ ANY MORE. The tests no longer use radioactive materials. They are tests for specific IgE.

               These blood tests for allergy are generally less sensitive, more expensive, and the results are not immediately available.

               Threshold values for food specific-IgE have been established for a few foods. When the value exceeds the critical cutoff value, there is an increased risk of a reaction. Only a few foods have these critical cutoff values established.

               Note that an undetectable specific IgE by an immunoassay has a low negative predictive value. Reactions can occur in 10-25% of patients who have undetectable specific IgE to a food.

Managing  Food Allergy

• Current management involves the following. Anything else is experimental.
• Avoidance
• Education
• Medical alert jewelry
• Medications for reactions- epinephrine, diphenhydramine

Experimental treatments

• Humanized monoclonal anti-IgE- use limited in food allergy
• Oral Immunotherapy- recent work suggests this may induce tolerance

The Oral Immunotherapy must be considered investigational- more studies are needed to address the effect and the safety of this form of treatment.

The Role of Food Allergy in Eosinophilic Esophagitis (EE)

This is a clinical condition that has increased in frequency. Symptoms include; difficulty feeding, failure to thrive, vomiting, epigastric/chest pain, dysphagia, and food impaction.

The diagnostic criteria are;          

• Clinical symptoms
• >15 eosinophils per high powered field on biopsy
• No response to a proton-pump inhibitor for 1-2 months or a normal pH probe study
• Exclusion of other causes

The cause of this condition is not completely understood. Atopy (tendency towards allergy) has been implicated as a factor with >50% of EE patients having an atopic condition. Most patients improve with either dietary restrictions or elemental diets, so food sensitization appears to play a role.

A review of responses to dietary manipulation revealed the percent of patients who had symptom improvement/resolution from 96-100% in four studies that used an elemental diet and 57-94% improvement/resolution with restricted or 6- food elimination diets. A study with only wheat or rye avoidance demonstrated only 17% with improvement/resolution.

How to identify potential food triggers of EE

               Potential food triggers have been hard to identify in EE.

               A recent consensus report did not recommend in vitro food allergy testing (specific IgE) due to a lack of positive or negative predictive values for food-specific IgE level testing in EE. Furthermore, the absence of IgE does not eliminate a food as a potential trigger. Non-IgE mechanisms may play a role.

               With skin prick testing, 2/3 patients with EE had positive reactions to at least one food such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.

               Atopy patch testing may show some usefulness in identifying foods that may elicit a non-IgE response.  Currently these types of tests are not validated and have only been evaluated in a very small number of studies (these are all from the same research group). There are no standardized materials, methods of application, or interpretation of results. Also, importantly there has been no study that has included a control (non-sick) population to validate atopy patch testing.

Reviewers comments- This was a fun article to read and review for you. Two huge areas, food allergy and eosinophilic esophagitis were condensed in a very scholarly fashion. This is a contemporary review that included many references. It eagerly and cautiously points out strengths and weaknesses of what is going on in diagnostics for food allergy problems. I applaud the points made about blood tests for allergy especially the limitations for their use in EE. There is interest in patch tests for food reactions, however the major proponents of its utility tend to be from only one group that publishes on the topic. The patch testing for foods does need validation in the proper population.

For those of you who are interested in food allergy, you should look at this article.

FEL