This week I am presenting at a seminar at the Riley Child Care Conference. The seminar was the idea of Dr. Sandeep Gupta (pediatric gastroenterology). The title is “Puzzling, Perplexing, Problematic Allergies in Children”. The third lecturer is Dr. Jeff Travers (dermatology). I have the task of talking about allergy testing and referral to the allergist. Food and specifically food allergy is the common ground for the three specialties. My focus will be on food allergy evaluations and management.

I have been putting this presentation together for a number of weeks. I was ahead of deadline and sent my slide copy and handouts to the organizers for inclusion in the syllabus. For those involved in continuing medical education (CME) programs, that is what is called being a good citizen. However, I just changed major parts of my talk due to the appearance of an article in the Journal of the American Medical Association (JAMA) this past week. The article is entitled ‘Diagnosing and Managing Common Food Allergies: A systematic review’ by J Schneider Chafen and colleagues (JAMA, May 12, 2010- Vol 303, No 18, pages 1848-1856). I know that I am in trouble for doing this because showing slides that are not part of the syllabus has always been a most dangerous behavior for a CME speaker. The audience tends to yell at the speaker for this violation, however I will take the hits in favor of providing the most up to date information.

The idea of a ‘systematic review’ is a very specific and intense look at the literature on a specific topic. First a few basic questions are established. This is followed by an extensive review of everything in the literature on the topic/question. There are strict inclusion criteria. The data from the studies is abstracted, the quality of the study is assessed, and the data is then synthesized. The hope is that those studies which have substantial numbers of cases in randomized controlled studies were evaluated and included in the review. This is done to present the best, the most valid, and most convincing work.

This systematic review caused me to revise my talk and add seven slides that will truly reflects the most current information.

This review was sponsored by the National Institute for Allergic and Infectious Diseases (NIAID). It is the prelude to the establishment of National Food Allergy Diagnosis and Management Guidelines, a topic I have talked about previously. There were 12,378 literature citations on food allergy found between the January 1988 and September 2009. From this, only 72 articles qualified for this review. That represents approximately 0.05% of the starting total. This is important to note. Almost all of the articles pulled did not fit the purpose of this review. The specific topics that were sorted inclluded; food allergy prevalence, studies of diagnostic tests, and studies on management and food allergy prevention. Further restriction involved looking at studies that dealt with specific food allergies; milk, egg, peanut, tree nut, fish, and shellfish (50% of all food allergy).

The overall summary was that the literature/evidence regarding food allergy prevalence, diagnosis, and management is voluminous, diffuse, and according to this review is also critically limited by the lack of uniformity on what food allergy is (lacking uniformity for criteria for the diagnosis of food allergy). The point is that when looking at an article on food allergy we have to be sure what is being talked about. All too often the diagnosis is based on laboratory study results alone. This lack of defining food allergy has severely limited making conclusions regarding the best practices for managing and preventing food allergy.

It may come as a surprise, but food allergy has no universally accepted definition. The NIAID suggested definition is “an adverse immune response that occurs reproducibly on exposure to a given food and is distinct from other adverse responses to food, such as food intolerances, pharmacologic reactions, and toxin-mediated reactions.

The results were as follows;

• Prevalence- food allergy affects more than 1-2% of the population but less than 10%.
• Diagnosing- food challenges, skin prick tests (SPT), & serum food-specific IgE (blood tests for food allergy) all have a role in making the diagnosis, but no one test has sufficient ease of use or sensitivity or specificity to be recommended over the other tests. The food challenge suffers from not being easy to use in general clinical practice.
• Management (elimination diets)- only 1 randomized controlled trial (RCT), established as the more scientifically rigorous test,  was identified for the effect of elimination diets. RCT are generally lacking for atopic dermatitis and eosinophilic espophagitis. The benefits for elimination diets are uncertain based on published evidence, and potential benefits need to be weighed against the potential nutritional risks especially in children. It is important to point out that this is not referring to trials for serious life-threatening food allergy reactions, such a trial would be unnecessary and unethical.
• Immunotherapy- not a currently licensed method for treating food allergy. May be effective in generating desensitization. The effect on long-term tolerance needs to be determined.
• Prevention- In high-risk infants hydrolyzed formula may prevent against cow’s milk allergy, but standard definitions of high risk and hydrolyzed formula do not exist.

There were a few general comments made that are worth noting.

• There is the potential for the over-diagnosis of food allergy
• Consequences

                Dietary restriction

                Nutritional problems

                Anxiety/worry

                Social challenges due to food allergy

There were a few final comments in this paper that are worth consideration.

• Proper interpretation of SPTs and serum food-specific IgE results requires evaluation of the data within the context of the clinical history and physician understanding of symptoms consistent with clinical food allergy to separate true positives for food allergy.
• The over-diagnosis or misdiagnosis of food allergy by medical practitioners obscures the substantial morbidity caused by patients truly affected by immune-mediated food allergy and serves to perpetuate some public misperceptions that food allergy is a trivial medical condition.

We all have a significant amount of work to sort this all out. The first steps are coming to some consensus as to what a food allergy is and what it is not. We then need to perform a detailed medical history to tease out a reproducible immune response with exposure to a food. Next we need a diagnostic tool or tools to be used to confirm our impression. The food challenge has been the gold standard for this, however it is not easy to perform food challenges. The next need is a plan of management. There has always been avoidance. We can add ‘Father Time’ as some food allergies can be outgrown. We eagerly look forward to immunotherapy that not only provide desensitization but will lead to tolerance.

FEL

We talked about the findings at the meeting. We shared  experiences and concerns and we talked about a number of great ideas to help children with food allergy. One of the most thought provoking topics was looking at food allergy as a public health problem. This is definitely a public health problem. As an aside, the request for comments on the ‘ Food Allergy Mangement…’ draft began with a very effective attention getting statement-’Food allergy is an important public health problem….’ . To my dismay (that recent Masters of Public Health degree affecting my perspective again), the guidelines’ intention was to help with diagnosing and managing food allergy and not the public health issues. I applaud this work and the work of the committee that put this together. I have never made any responses to requests for comments on guideline drafts in the past. This draft of the guidelines stimulated me to offer a few comments. The acceptance of these food allergy guidelines is  important and desperately needed before we can be effective in any public health approach to food allergy. We need to critically look at what food allergy is and what is not food allergy. We need to listen to the story of what happens with exposures to food and carefully select the appropriate tools/tests to make the diagnosis. We also need to support efforts to help treat current food allergy issues and hopefully prevent the development of food allergy.

I shared with the group a review by Scott Sicherer on ‘What is New in Pediatric Allergy’. In this session Dr. Sicherer selected a few key articles that have appeared over the past year dealing with food allergy. A few of the food allergy topics included; The Natural History of Wheat Allergy (Keet, 2009), Food Protein-Induced Enterocolitis Syndrome (Mehr, 2009), Timing of Food Introduction and the Development of Atopy (Nwaru, 2010), and Dietary Advice, Dietary Adherence, and the Acquisition of Tolerance in Egg-allergic Children (Allen, 2009).

1. Wheat allergy resolved faster than egg or milk allergy.

2. FPIES- depending on the population studied, different foods are causitive and there seems to be differences in the rate of resolution. The overall prognosis is good.

3. Sensitization (having a positive allergy test, not necessarily symptomatic with exposure) was seen with the late introduction of a number of foods in this cohort of children from Finland.

4. Dietary advice is not uniformly followed, the advice given did not correlate with outgrowing egg allergy, adherence to the advice did not correlate with resolution, and accidental exposures to egg did not affect the outcome (outgrowing the allergy).

We also talked about research projects and protocols that involve food desensitization and food tolerance. Wes Burks from Duke University presented information on a number of studies. This work is ongoing at Duke, University of Arkansas, and at Mt.Sinai (New York). It is important to understand the differences between achieving a state of desensitization or tolerance.

1. Desensitization is the temporay increase of the amount of a food that would trigger an allergic reaction. This would offer protection from a life-threatening event due to an exposure.

2. Tolerance is the permanent loss of allergic reactivity due to changes in the immune system.

Desensitization and tolerance may work through similar mechanisms. Small exposures would not cause life threatening events in the desensitized child, however only the tolerant child could eat larger amounts of the culprit food without consequences.

The enthusiasm for participation in studies that may end the fear of a food reaction was intense. I was very impressed. A mother mentioned that she would donate her home if her child could participate in a program that would lead to desensitization/tolerance for peanut.

I shared the findings from an abstract of a study from the University of Michigan (abstract # 746). This was a report from a survey that represented the US population. In this survey 3-4% of those responding had a child with a life-threatening food allergy. Twenty five percent of responders knew someone with a food allergy. Of the families who had a child with a food allergy, 80% were accommodated by the school or daycare and of those, 50% of the staff had specific training in food allergy. Nearly 50% of the responders said that they were not at all inconvenienced by measures needed to protect the food allergic child, 25% were somewhat inconvenienced, and a few said it was very inconvenient for them.

We spent some time talking about this. Some of us were surprised by the findings. The charge to the group and the charge to anyone involved with children with food allergy is to advocate and to make others aware of the issues. The Southside Food Allergy Support Group offers an excellent program called
PAC- Protect Allergic Children. PAC has a detailed presentation that can be given in a number of venues.  The programs are ‘Food Allergy Safety in Schools’ and ‘Creating a Safe Home for Food Allergic Families’. Information on these programs can be obtained from the Southside Food Allergy Support Group.

One topic for a future meeting most certainly will be a summary of the final Food Allergy Guidelines.

My thanks to the Southside Food Allergy Support Group for the invitation to speak (as a disclosure, I am an advisor to the group as well). Keep the kids safe!!

Respectfully submitted,

Fred Leickly

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

We have seen many children who were evaluated for food allergy and/or who were brought by parents to be evaluated for food allergy because of redness to the cheeks that is observed after eating.

What I haven’t heard about is a syndrome called ‘Frey’s Syndrome’. 

In the January edition of Postgraduate Medicine there is a case report, pictures, and a review of this syndrome which frequently precipitates an allergy evaluation. The problem is not due to allergy. It is an allergy-pretender.

Frey’s syndrome is also called the auriculotemporal nerve syndrome.  It involves redness over the cheeks after eating or drinking. The cause is abnormal nerve regeneration which can happen with forceps delivery or after parotid-gland surgery.  The actual incidence of the syndrome is unknown and it is by this report rare in children. Sucking on a lemon brings out the facial flushing. The use of starch/iodine brings sweating which is seen more in the adult.

The facial flushing with eating, gustatory flushing, may mimic food allergy and lead to unnecessary testing and the consequence of restrictive diets.

The clinical course is benign in children. The authors point out that it is important to recognize it so unnecessary evaluations are avoided.

The treatment is explanation and reassurance.

If you can see the paper, there  pictures of this flushing. The reaction looks distinctly delineated. It follows the distribution of the nerve.  The young lady would experience the flushing after eating sweets, citrus fruit, grapes, tomato sauce, fruit-flavored ice cream, and spicy foods. She had no history of any trauma to the area of the auriculotemporal nerve. There were no other symptoms besides this flushing. There was no personal history of allergy. Her teachers thought that this was a food allergy issue. In the clinic, the flush was seen one minute after eating a citrus-flavored sweet.

 I had not heard of Frey’s syndrome before, but I have seen a good number of red-cheeked children who had no other signs/symptoms of a food allergy. In this case, the types of food that elicited the problem, the timing of the flush in relation to eating, and the specific distribution help with the diagnosis of Frey’s syndrome.

We will start stocking sweet citrus-flavored candies for test purposes only. I am soliciting suggestions. So far I think Skiddles may work. If you can think of a candy that is has more of the citrus bite, let me know.

My thanks to the authors N Hussain, M Dhanarass, and W Whithouse for this article (Postgraduate Medicine Journal January 2010 Vol 86 N0 1011 page 62.)

Fred Leickly

Last week I was interviewed by a reporter from the Wall Street Journal. The topic was food allergy. The reporter came across this website and thought that I be a good resource for her article. We had a delightful talk that went on for 45 minutes. Questions were asked about the increase in food allergy; is it real or is it possibly due to the over use of diagnostics (allergy testing).

Needless to say I was excited about the prospect of being quoted in the Journal.

My hopes were dashed. The reporter had to cutback on material. My name did not appear in the article. The article was very well done and did quote a number of outstanding leaders in the field of food allergy (Drs. Hugh Sampson and Robert Wood).

I do encourage you to read the article written by Melinda Beck.

FEL