The July issue of Pediatrics has an article entitled, ‘The Prevalence, Severity, and Distribution of Childhood Food Allergy in the United States’ by R S Gupta, E E Springston, M R Warrier, B Smith, R Kumar, J Pongracic, and J L Holl. The bottom line from this work is that the prevalence and severity of food allergy is greater than previous reports would indicate and this was a fairly large nationwide survey designed to address the question of prevalence. The authors also conclude that disparities exist with the clinical diagnosis of the condition.

Purpose of the paper- to determine the prevalence, severity, and distribution of food allergy in children.

Methods-The authors created a survey that was population-based and cross-sectional. It was administered to a representative sample of the United States population between June 2009 and February 2010. This survey was carefully developed and evaluated prior to its use. It was not a previously used, standardized tool.

Recruiting and survey administration was performed by a survey research company. Internet access was required to participate.

Completion of 40,000 surveys would give the study significant power (0.9) at a significance level of 0.5 to detect overall and allergen-specific food allergy prevalence (between 1-9%) and prevalence variability from 1-7% in groups as small as 1% of the sample.

Outcome Measures

The primary outcomes were food allergy prevalence and severity.

Food allergy was defined as a report of a confirmed or a convincing story of an allergy.

A convincing food allergy was based on at least one of the following;

1. Anaphylaxis- defined as a severe reaction that could lead to death
2. Angioedema (swelling) of the lips, eyes, or face
3. Other Angioedema
4. Coughing
5. Other oropharnygeal symptoms
6. Eczema
7. Flushing
8. Hives
9. Low blood pressure
10. Pruritis (itching)
11. Trouble breathing
12. Vomiting
13. Wheezing

A confirmed food allergy had the above criteria and included a report of a physician-diagnosis with serum-specific IgE, skin prick test results, or the result of an oral food challenge.

The severity of a food reaction was based on the nature of the symptoms;

Mild-moderate food allergy symptoms were limited to;

1. Angioedema of the lips, eyes, or face
2. Other angioedema
3. Coughing
4. Other oropharyngeal symptoms
5. Eczema
6. Flushing
7. Hives
8. Pruritis
9. Vomiting

Severe food allergy symptoms were;

1. Any report of anaphylaxis
2. Low blood pressure
3. Trouble breathing
4. Wheezing
5. Vomiting and angioedema, and coughing in combination

Results

The final sample size was 38,480 children.

The prevalence of food allergy in children was 8%. Multiple food allergies were reported in 2.4% (approximately 1/3 children of those with food allergy had more than one food to report).

Allergen prevalence was as follows;

Peanut- 767/3339 (23% of the reports) 52% had severe reactions, 48% had mild-moderate reactions

Milk- 702/3339 (21% of the reports) 31% had severe reactions, 69% had mild-moderate reactions

Shellfish- 509/3339 (15% of the reports) 47% had severe reactions, 53% had mild-moderate reactions

There was an age variation reported (the highest percentage reporting a specific food allergy);

Peanut- 30% in the 3-5 years of age group

Milk- 32% in the 0-2 years of age group

Shellfish- 24% in the > 14 year old age group

Tree nuts- 15% in the 11-13 year old age group

Egg – 16% in the 0-2 year old age group

Fish (fin) – 7% in the >14 year old age group

Strawberry- 8% in the 0-2 year old age group

Wheat- 8% in the 11-13 year old age group

Soy- 7% in the 11-13 year old age group

Severity of the Food Reactions

The prevalence of a severe reaction to a food was 3.1% of the surveyed population. This translates to 38.7% of the food allergy population. These severe reactions were reported more frequently in the children who had peanut or tree nut allergy. From the note above- 52% of the peanut and 53% of the tree nut allergic group had severe reactions.

When it happens to you or your child- it is 100%. The reassurance factor- just over 1/3 have serious reactions, most do not. Serious reactions are seen just over half the time with peanuts and tree nuts.

Food Allergy Associations- Odd/Risk Factors

The odds of having a food allergy were-

1. Higher in Asian and black children as compared to white children.
2. Higher in all age groups compared to children aged 0-2 years.
3. Higher in geographic areas outside the Midwest.
4. Lower with household incomes <$50,000.
5. Gender did not make a difference
6. Higher for a confirmed food allergy compared to a convincing food allergy history in those children with multiple food allergies.
7. Lower for confirmed food allergy in Asian, black, and Hispanic as compared to white children.
8. Lower for confirmed food allergy in households with incomes <$50,000.
9. Higher for a severe reaction among children in all age groups compared to children 0-2 years of age,  boys compared to girls, and those with compared to those without multiple food allergies.

Conclusions

Eight percent of children have food allergy with 38.7% having a severe reaction and 30.4% having multiple food allergies.

The disparity regarding food allergy diagnosis was seen with race, age, and income.

Reviewer’s Comments

Prevalence refers to the proportion of individuals with the clinical condition in a population at a specific moment in time. It provides an estimate of the risk or probability that an individual will have the condition. This would be the number of cases divided by the total population at a given moment.

When looking over the information there are a few points that need to be stressed. First was the sample truly representative?

The study was not performed on the entire pediatric population of the United States. The population was recruited from 6100 participants through a Web-enabled panel and an additional 33,900 came from on online sample of households with children; they all had access to the internet. This specific population is reported to be representative of U.S. households with children. So the first concern has been answered. However, a question arises as to selection bias. Do families who have children with food allergy have more computer access? Did the lack of computer (internet access) lead to non-selection for the study?

The second point was the definition of a food allergy. This was by the family’s report of a reaction or a confirmed food allergy. This was not a medical record review nor was this a bone-fide food challenge. The authors do point out that another bias; recall bias may be at work.

This was the largest study conducted looking at food allergy prevalence- a uniqueness to the work.

The article points out a number of helpful ‘between the lines’ points. About half of the children with a peanut allergy had a severe reaction. You can have mild-moderate reactions to peanut. The same relationship was seen with shellfish allergy.

The authors used multiple logistic regression models to establish odds. This statistical tool looks at the degree of association between having the condition after adjusting for factors that may be confounding. When the odds equal 1, then there is no increased/decreased relationship. When confidence interval include the number one, then there is no strong statistical difference. There seems to be a tendency for disparity, however I would be cautious due to the stated confidence intervals. The disparities that look clear are

Race- Asian, Black for having food allergy

Less confirmed vs. convincing cases with Asians

Age-compared to two year olds, more food allergy in all other ages

Age- compared to two year olds, more severe food allergy in all other age groups

Income- household income lower than $50,000 was protective for having food allergy, for having fewer confirmed vs. convincing histories, and having less severe food allergy. (In these instances the odds was less than one)

Geographic regions- compared to the Midwest, there was more food allergy in the Northeast, South, and West.

As for summarizing discrepancies in a few sentences- if the child was Asian or Black there was a higher chance of having food allergy, and less of a chance that it was confirmed if the child was Asian. Children over the age of two years have more reported food allergies and they tend to be more severe in the older age groups. If your family made less than $50,000, there was less of a chance that there would be a food allergy (poverty protects?). Lastly, there is less food allergy in the Midwest that in other regions of the country.

I enjoyed reading and reviewing this article. As with many good studies it stimulates more questions.

Respectfully submitted,
FEL

 My first draft of this was longer than the summary! I needed to trim my commentary so what follows are the new ideas, the controversial issues, and perhaps some of the iconoclastic issues- clearly there needs to be changes in how food allergy is approached. Many of our thoughts and recommendations desperately need updating and change.

As with more recent guidelines, this is an evidence-based report that provides recommendations when there is strong evidence to support an action and makes suggestions when the expert panel recommendations are somewhat weak based on the evidence available.

The evolution of the scientific evidence used is of note; 12,300 titles of articles were screened, 1,200 of these were reviewed,  900 articles were abstracted, and 348 articles helped form the final guidelines. What that means is that a significant amount of work went into this document. (This is an important point- Is the advice given regarding food allergy coming from one’s training, experiences in clinical practice, or through the application of findings from investigation and publication of those findings in peer-reviewed journals?)

Here are some of the highlights- a summary of the summary. Items in bold italics are what I think are the key components. I have included only material that relates to children in this review. (My opinion/commentary appears in parenthesis.)

Definitions

                Food allergy is an adverse health effect due to a specific immune response that occurs reproducibly on exposure to that food.

                A food allergen is a component or ingredient of a food that is recognized by allergen-specific immune cells and elicit a specific immunologic reaction with characteristic symptoms.

                Sensitization  occurs when there are IgE antibodies to the food, but no symptoms with exposure. Sensitization alone is not enough to declare a food allergy. Food allergy requires sensitization and symptoms with exposure.

                Reactions to foods can occur without involving any immune mechanisms. These are food intolerances.

Natural history of food allergy in children

            Most will eventually tolerate milk, egg, soy, and wheat. The timeline to tolerance depends on the food. High specific IgE levels at the time of diagnosis (blood test results) are associated with not outgrowing the allergy.

                Decreasing levels of specific IgE to foods has been associated with the ability to tolerate the food.

                (We see the specific IgE or blood test for food allergy as a predictor of the natural history of a food allergy. A specific blood level of IgE antibody to a particular food helps predict the risk of a reaction. The blood test is used to decide on doing a food challenge.)

Risk factors for developing food allergy in children

            A family history of atopy and having atopic dermatitis are risk factors for sensitization to foods (positive tests) and food allergy (positive tests and symptoms with exposure). (A child with atopic dermatitis and with a sibling or a parent with atopy is at risk for developing a food allergy.)

Risk factors for the severity of an allergic reaction to foods

            Allergic reaction severity is due to many things, however the severity of a reaction cannot be predicted by the severity of a previous reaction . The severity of a reaction cannot be predicted by the amount of specific IgE nor by the size of an allergy skin test. (So it would be inappropriate to say that a child is severely allergic based on the size of a skin test or by the level of a blood test. The severity is what happened with the exposure.)

                Severe reactions occur more often when the co-morbid condition of asthma is present. (Another very good reason for a child with asthma and food allergy to be managed by an allergist,)

Diagnosing a food allergy- The medical history and physical examination

            A detailed history helps decide if it is an allergic reaction and the type of allergic reaction. It is also used to identify the culprit/suspect food.

 (You have to talk to people when you are an allergist. The conversation dictates the nature of the tests. All too often we have a child who has had tests done and no story to support the testing.)

Methods to Identify the causative food- Allergy testing

            Skin prick tests are recommended to help identify foods that may cause an IgE-mediated food reaction. The skin prick test alone is not considered diagnostic of a food allergy.

            Intradermal skin testing (using a needle and injecting the material within the skin) should not be used to diagnose a food allergy.

            Specific IgE (blood tests) for food allergy are recommended to help identify foods that may cause an IgE-mediated food reaction.  Specific IgE tests used alone, are not diagnostic of a food allergy.

            Food allergy patch testing should not be used in the routine evaluation of non-contact food allergy. (Some foods can cause a contact dermatitis for which patch testing can help with the diagnosis.)

Food elimination diets

            Eliminating one or a few specific foods may be useful in diagnosing a food allergy. This may be especially useful in identifying foods responsible for non-IgE- mediated reactions. The blood tests and the skin prick tests are used for IgE antibody detection. Foods can cause problems through other mechanisms. Unfortunately, there are no diagnostic materials for these other reactions. For conditions such as FPIES, Heiner Syndrome, and eosinophilic esophagitis an elimination diet may help.

Oral food challenges

                A food challenge is recommended for diagnosing a food allergy. When a food challenge causes symptoms and those symptoms correspond to history of food reactions, and there is evidence of sensitization from allergy testing, then at this point a diagnosis of a food allergy can be made.

Nonstandardized and unproven procedures

            The expert panel listed 12 tests that have been used to diagnose IgE-mediated food allergy. Of note that Allergen specific-IgG4 is on this list.

The diagnosis of non-IgE-mediated immunologic adverse reactions to food

            The report suggests that skin testing, blood testing, and patch testing may be considered in identifying foods associated with eosinophilic esophagitis, but these tests alone are not sufficient to make the diagnosis of a food allergy. The role of these tests has not been established in other eosinophilic gastrointestinal disorders.

The diagnosis of IgE-mediated contact urticaria (hives)

                The medical history and supportive allergy tests help make the diagnosis. There are two forms of contact hives due to foods. Reactions due to IgE can be localized or systemic (involving other parts of the body and other organ systems). In the non-IgE-mediated form of contact hives, systemic symptoms are rarely seen.

                (This is a common concern in children. Food generally is not intended to be worn on the skin. If contact causes a hive and there is specific IgE demonstrated by allergy testing, then there is a risk of a systemic reaction. If the allergy tests [(blood or skin prick tests] are negative, then the risk of a systemic reaction is low.)

Management of non-acute allergic reactions and prevention of food allergy

            Individuals with documented IgE-mediated food allergy should avoid the food. Avoidance of the food is the recommendation for non-IgE-mediated reactions to food.

                Individuals with proven food allergy and who also have atopic dermatitis, asthma, or eosinophilic esophagitis should avoid their specific allergen(s).

                For individuals without proven food allergy, the guidelines does not recommend avoiding potentially allergenic foods for managing atopic dermatitis, asthma, or eosinophilic esophagitis.

When to re-evaluate

            This will depend on the specific food involved, the age of the child, and the interval medical history.

Pharmacologic prevention of food allergy

                No medications are recommended to prevent food allergy.

Immunotherapy for food allergy

            These guidelines do not recommend allergen-specific immunotherapy to treat IgE-mediated food allergy.

Management of individuals at risk for food allergy

            An ‘at risk’ patient are those who have a biologic parent or sibling with a history of or with current nasal allergy, asthma, atopic dermatitis, or food allergy (Mother, father, brother or sister with these conditions places a child at risk. Grandparents, uncles, aunts, and cousins are of interest but do not put the child at increased risk. ) Those at risk for food allergy- do not limit exposure to dust mites, pollen, or pet dander for the ‘at risk patient (child)’-

                Do not limit exposure to food that may be cross-reactive with the 8 major food allergens (United States relevant population); milk, egg, peanut, tree nuts, soy, wheat, fish, and crustaceans.

                There is insufficient evidence to recommend food allergy testing prior to introducing highly allergenic foods (for example milk, egg, and peanut) in children who are at high risk. There may be some value in doing an oral food challenge in those who have certain risk factors; sibling with a peanut allergy or evidence of another underlying food allergy. The example here was finding positive tests to tree nuts when the history was only positive for peanut.

                The widespread use of allergy skin tests or blood tests are not recommended due to their poor predictive value. “These tests would lead to many clinically irrelevant results and unnecessary dietary restrictions, especially if unconfirmed by oral food challenges”.

                These guidelines suggests that the general population of children not be tested for food allergy to highly allergenic foods prior to their introduction into the diet.

Testing infants and children with persistent atopic dermatitis

            Children less than 5 years of age with moderate to severe atopic dermatitis should be considered for a food allergy evaluation for milk, egg, peanut, wheat, and soy if at least one of the following criteria is met;

                1. The child has persistent  atopic dermatitis in spite of optimizing management and topical therapy.

                2. The child has a reliable history of an immediate reaction after ingesting a specific food.

(This is a major change from the usual clinical approach to the child with atopic dermatitis. Pursue very specific foods only and only in moderate to severe disease who despite appropriate treatment and adherence to the treatment program is not improving.)

Prevention of food allergy

            No recommendation for restricting the maternal diet during pregnancy or lactation.

                Exclusive breast-feeding until 4-6 months unless breast-feeding is medically contraindicated.

                No use of soy in lieu of cow’s milk formula.

                Hydrolyzed infant formula vs. cow’s milk formula may prevent food allergy.

                No need to delay solid food beyond 4-6 months of age. Potentially allergenic foods may be given at this time as well.

It would appear that this summary of a summary is almost as long as the original document. I have made emphasized a few points and issues regarding food allergy that we see commonly hear about in our practice.

These are guidelines and not the law. They evolved from an extensive review of the literature and are evidence-based so there is experience and peer-reviewed scrutiny of the information used. These are recommendations and suggestions to guide us in diagnosing and managing food allergy.

I do foresee us doing more food challenges based on these recommendations. An early posting shared some of our experiences with doing food challenges.

Also, according to the NIAID link, in early 2011 a ‘lay’ version of the guidelines will be available.

Fred Leickly

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

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

N. Nicolaou, M Poorafshar, C Murray,  A Simpson, H Winell, G Kerry, A Woodcock, S Ahlstadt, and A Custovic.  Journal of Allergy and Clinical Immunology(JACI) 2010;125:191-7.

This article appeared in the most recent JACI. Almost as soon as I read the article, I began to put together this review (I am excited about the approach and ideas in this work). This paper states very clearly the problem of positive allergy tests for peanut (sensitization) and demonstrating clinical relevance- that is allergy to peanut. It addresses this problem using a new test for determining sensitization, component-resolved diagnostics.

Background:

          A few very important facts are noted about peanuts;

            1. Peanut is a nutritious and inexpensive food

            2. Peanut is one of the most common food allergies

            3. The prevalence of peanut allergy is increasing

            4. Peanut allergy is usually life-long

            5. Peanut avoidance is the current management of this allergy

            6. Accidental peanut exposure is common

            7. Peanut exposure in the allergic child can be life-threatening

Peanut allergy diagnosis issues:

            1. An accurate diagnosis is very important- sensitized or truly allergic?

            2. The gold standard for the diagnosis of peanut allergy is the

               ‘double-blind placebo-controlled food challenge (DBPCFC)

            3. DBPCFC are costly, time consuming, and dangerous

            4. The diagnosis is made with a suggestive history of what happens after exposure,

                supported by a skin prick test or by the determination of specific IgE in the blood

            5. These tests detect the presence of antibody (sensitization)

            6. Positive allergy tests does not equate to the presence of allergic symptoms after exposure-

                known as clinical allergy

            7. Current tests –both skin prick tests (SPT) and specific IgE tests (sIgE-blood) use crude peanut

                 extracts and contain a mix of the allergic proteins and non-allergic proteins that may

               cross-react with other allergens.

            8. Bottom line- peanut sensitization may not equal peanut allergy

Solving this problem:

            1. A new blood test to detect antibody production by the child to the important proteins in peanut that cause

                allergic symptoms has been developed

            2. This is called component-resolved diagnostics (CRD) – developed by Phadia

            3. This may be a more accurate tool to assess food allergy (vs. sensitization)

The purpose of the paper was to look at the CRD to correctly identify children with peanut allergy.

Methods:

A birth cohort of children enrolled in the Manchester Asthma and Allergy Study (Manchester, England) was evaluated. Information on exposure and reactivity to peanut was collected.  Peanut sensitization was measured by skin prick testing and by Phadia specific IgE.

There were 110 children (cohort contained 1085) who were sensitized and were asked to undergo a more extensive evaluation of their reactivity to peanut. This included more extensive history, skin testing, specific IgE, a DBPCFC, and the CRD.

The definition of peanut allergy included two very specific sets of criteria.

                        1. Sensitization and a positive oral challenge or

                        2. A convincing history and specific peanut IgE >15 kU/L and/ or a skin prick test that was greater than

                           an 8 mm wheal (this group did not have an oral challenge).

Results:

The cohort included 1085 children, 1029 were evaluated at age 8 years. There were 17 (1.6%) who had a history of peanut allergy.

Skin-testing was performed in 919 of the children with 47 (5.1%) having a positive SPT. Sensitization to grass pollen was noted in 59.6% of the children.

Blood studies were performed on 582 children with 71 (12.2%) having a detectable level of specific IgE to peanut. Grass sensitization was found in 67 (94.4%).

Overall, of the 933 children who had either a SPT or sIgE 110 or 11.8% were considered to be sensitized to peanut.

From this group of 110, 108 agreed to participate in the program. Seventeen did not consent to a food challenge. From the remaining 91 children, 12 had convincing histories and SPT/sIgE criteria to fit the definition of peanut allergy. Food challenges were performed in 79.

In the 79 oral food challenges to peanut, 66 had no symptoms with the exposure. Of the 13 who developed symptoms, 7 had two or more signs/symptoms and were declared peanut allergic. The breakdown on these number was- 66 were peanut tolerant and 19 were had peanut allergy (12 not challenged plus the 7 with a positive challenge).

The proportion of children with peanut allergy among those sensitized was 22.4%.

Peanut allergic and peanut tolerant children were compared.

            1. Asthma, eczema, and food allergies were more common in the peanut allergy group.

            2. Allergic rhinitis was more common in the peanut tolerant group.

            3. Peanut tolerant children had lower peanut sIgE and higher grass sIgE.

The CRD results differentiated the peanut allergic from the peanut tolerant group. The peanut allergic group had higher values to the major peanut proteins Ara h 1-3. The peanut tolerant group had higher reaction values to grass components. The response to the peanut protein Ara h 2 was the best discriminator.

A model was developed to discriminate between children with peanut allergy and peanut sensitization. The model misclassified only 2 (6.9%) with peanut allergy and 4 (7.7%) peanut tolerant children.

Conclusions:

The majority of children who have peanut sensitization based on SPT or sIgE do not have peanut allergy. The CRD may help the diagnosis of peanut allergy.

Reviewers Comments:

This is exciting work. In the practice of allergy we struggle with positive tests and their clinical relevance. The authors very clearly point out the differences between sensitization and allergy. The test makes no one allergic. The test only tells us that specific IgE is being made. The history and/or a food challenge help define that clinical relevance in making the diagnosis of food allergy.

Phadia has developed a very specific assay which will help in making the diagnosis of peanut allergy. I am excited about the prospects for CRD. Phadia’s science is at the cutting edge of food allergy and I look forward to using this assay for the large number of children we see in our practice with a positive test for peanut antibody. I have always had the greatest respect for Phadia’s science; it is the marketing part that I have issues with (topic of a few of my posts).

The authors point out the strengths of this study. They performed a very extensive evaluation and used the DBPCFC for verification.

The small number of children reported is a recognized weakness. The authors encourage replication of their work.

The study looked at 8 year old children. I wonder about why that age and from the paper my guess is that this was the most recent year of evaluation on their cohort. This birth cohort attended the clinic at ages 1, 3, 5, and 8 years. In our clinic we use age 5 as our cut-off for peanut challenges. At this age, most children are able to communicate with us regarding the subtle aspects of allergic reactions.

Look at the rate of positive tests for peanut. The testing of a population of children revealed that almost 12% will have a positive test for peanut.

The last paragraph in the paper goes as follows; “The majority of children within the general population with positive skin test or measurable serum IgE to peanut do not have clinical peanut allergy.

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

Authors: Amy Branum and Susan Lukacs

Reference: Pediatrics Volume 124 (6) December 2009

This title caught my eye. The impression in clinical practice is that more and more children have food allergy. This article looks at the prevalence of food allergy in children. I wanted to get this review posted this week. I am off to Santa Fe to moderate an AAP Practical Pediatrics Course. This AAP meeting is similar to the one I reported on earlier on this home page (Rhode Island). This meeting has an excellent cast of presenters. I plan to take notes and post a few updates upon my return.

Purpose of the article: To describe trends in the prevalence of food allergy and food allergy-related health care utilization in children in the United States.

Methods (how was this study conducted?): Data from a number of national health surveys were reviewed.

• Food allergy prevalence was evaluated in children 0-17 years of age from surveys conducted over the years 1997-2007. The question asked about food allergy was “During the past 12 months has the child had any kind of food or digestive allergy?”
• Blood tests for IgE antibodies to foods were taken from the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Specific IgE antibodies to peanut, egg, and milk were measured using the Pharmacia ImmunoCap 1000 System. Specific IgE to shrimp was measured only in children over the age of 6 years. The range of specific IgE values was 0.35 to 1000 kU/L.
• Information regarding food allergy-related visits to physician offices and hospital facilities was taken from two additional surveys.
• The results were analyzed using rather sophisticated statistical tools that included weighing the data for the analysis of trends.

Results (what the study found):

• The prevalence of reports of food allergy in children has increased from 3.3% in 1997 to 3.9% in 2007.
• Peanut IgE antibodies were found in 9.3%, egg IgE antibodies were found in 6.7%, milk IgE antibodies in 12.2%, and shrimp specific IgE was found in 5.2% of children.
• Ambulatory care visits for food allergies tripled between 1993 and 2006. Between the years 2003 and 2006 there were 317,000 visits/years to emergency departments and outpatient offices. Hospitalizations with a recorded diagnosis related to food allergy increased from 2600 to 9500 discharges/year.

Conclusions:

                These national surveys show that food allergy prevalence and/or food allergy awareness has increased in recent years.

Commentary:

                The authors point out a number of limitations in the study, however the major contribution here is reporting on what these surveys reveal about the parent’s report regarding food allergy. Food allergy may be rising however it is possible that the results may be due to increased food allergy awareness which is also a very good thing. This is a report of prevalence and does not go into the possible reasons for the increases.

                It is important to note that this was a survey. A simple question was asked. These were not absolutely proven cases of food allergy. The question included digestive allergy which has the potential to include a number of clinical conditions that are more common and may or may not be allergy; lactose intolerance, eosinophilic esophagitis, and celiac disease for example. This was a report on what a parent thought about food allergy in their child.

                The report has a few ‘between the lines’ issues as well. The conclusion is that food allergy and digestive tract allergy has a prevalence of 3.9%. The study also included a survey in which a blood test for allergy was performed. Using the blood test the prevalence of peanut, egg, milk, and shrimp ‘allergy’ exceeds the overall food allergy prevalence. The authors do point out this difference and are very careful about what is allergy and what sensitization to food is.  “Although serum IgE measurements cannot be used alone to determine the prevalence of food-specific allergies or to predict reactions to certain foods, they give an indication of increased atopy and risk for allergic reactions to food.” I define allergy and atopy on my allergy testing page.

                We also need to be a bit careful on the hospital data. The information on health care utilization included children who had a diagnosis of a food allergy. This did not necessarily mean that they were in the health care facility for a food allergy issue. There is a tendency in coding encounters to include as many codes as possible and to include codes that will help with health care utilization reimbursements.

                The statistical analyses on papers like this always fascinate me. During my MPH training I had a number of biostatistics courses. The weighing of the data is frequently done and when it is done, differences can be found. Sometimes it is interesting to see what the results were before any weighing. I have also wondered what went into the ‘weighing’ of the data. What elements of the data were assigned a ‘weight’ to make them work into the analysis?

                This was a nicely done paper and does answer some questions however as many quality studies also do it has us asking many more questions about food allergy in children.

Fred Leickly

I should be receiving my copy of the journal soon. I am concerned about how food allergy will be defined in the paper: will the diagnosis of food allergy be based on a history of exposure confirmed with appropriate allergy testing or will this be based on only laboratory results and no history?

As soon as I have this in hand I will post a commentary.

Fred Leickly