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Hope For Preventing Peanut Allergy- A Review of the LEAP Study

What the heck! You are telling me to give my scratchy, itchy, eczema-affected child and/or my child with egg allergy- PEANUTS? Has the world gone ‘topsy-turvy’?

This topic has gotten a significant amount of press. I have not looked at commentaries and editorials just yet so as to not to be swayed by other’s reviews in writing this post. I will look at them later and go forth with my take on this exciting study. I was at the AAAAI meeting in Houston (February 20-24th) where Dr. Lack presented this work as a Keynote speech.

You may recall posts and reviews from about two years ago that talked about not avoiding hyper-allergenic foods during infancy and early childhood, but starting them earlier in life in hopes of preventing a food allergy. This new study attacked the adage (adage defined by Webster as an old saying that has been popularly accepted as truth) about avoiding hyper-allergenic foods and has convincingly shown that the early introduction of a significant food allergen- peanut, prevents the development of peanut allergy.

The title of the paper is ‘Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy’. The lead author is George Du Toit and the senior author is Gideon Lack. This appeared in the New England Journal of Medicine 2015; 372:803-813.

Purpose of the Study- This is a report from the LEAP study- Learning Early About Peanut Allergy. The purpose of LEAP was to see if the early introduction of dietary peanut to infants would prevent peanut allergy.

Methods- The study was performed at one site (United Kingdom). The study was randomized, open-label, and controlled. Approval for the study came from the National Research Ethics Service Committee London-Fulham. Bamba was the peanut snack used for the infants.

This study enrolled infants from 4 to 11 months of age. They needed to have either severe eczema, egg allergy, or both.

Skin prick tests were performed for peanut. Two study groups were created based on the skin test results- negative skin prick test and positive (1-4 mm wheal). These two groups (peanut positive and peanut negative) were randomly split into two groups- peanut eaters and peanut avoiders.

Those infants who were in the peanut consumption group underwent a peanut challenge. If the skin test was negative, they received 2 grams of peanut as one serving. If the skin test was positive, the infant underwent a graded peanut challenge. If the child had a reaction during the challenge they were told to avoid peanuts.

Those infants in the peanut eating group were given at least 6 grams of peanut per week in three or more servings per week until age 5 years. Adherence to this diet was checked with a questionnaire and with some families, an analysis for peanut dust in the child’s bedding.

Clinical assessments occurred at 12, 30 and 60 months of age. Telephone interviews were weekly until age 1, every two week until 30 months of age and monthly thereafter.

Outcomes-the primary goal was to see how many of these children had peanut allergy at age 5 years. Peanut allergy was assessed by doing a peanut challenge.

The immune studies that were performed included; skin prick tests, peanut specific IgE, IgG, and IgG4.

Results-

Study Population- the median age for screening was 7.8 months. There was a 98.4% retention rate.

Peanut Consumption and Allergy in High-Risk Children-

There were 542 infants who had a negative skin prick test, 530 were included in the analysis. At 5 years of age 13.7% of the peanut avoidance group and 1.9% of the peanut consuming group had peanut allergy. This was an 86.1% decrease in peanut allergy prevalence.

There were 98 children who had a positive skin prick test to peanut. At 5 years of age, 35.3% of the avoidance group and 10.6% of the peanut consuming group were allergic to peanuts. This was a 70% relative reduction in the prevalence of peanut allergy.

Adherence

The median consumption of peanut in the avoidance group was 0 and in the peanut consuming group it was 7.7 grams (by questionnaire).

Dust samples from the bedding, an index of peanut exposure; 4.1 micrograms/gram of dust in the avoidance group and 91.1 micrograms/gram of dust in the peanut consuming group.

Safety

There were no deaths during the study. There were also no significant differences in rates of hospitalization or serious adverse events between the avoidance group and the peanut consuming group.

Almost all of the children (99%) had at least one adverse event. More events occurred in those who were consuming peanuts. The adverse events were of five different types; upper respiratory tract infection, viral skin infection, gastroenteritis, urticaria (hives), and conjunctivitis (irritated eyes). Most of these were mild to moderate. The specific IgE blood level did not distinguish more serious adverse events.

Response to Oral Food Challenge

A failed oral food challenge occurred in 7 children who were assigned to the peanut consumption group at baseline. These children did not consume peanuts and at age 5 years the oral food challenge was positive in four.

Nine children in the peanut consuming group discontinued eating peanuts. At 5 years of age, six of these children had a positive peanut challenge.

Seven who were randomly assigned to the consumption group had a positive response to the oral food challenge at baseline. These were mostly skin reactions.

The 57 who had a positive food challenge at 5 years; 14 had respiratory or cardiovascular sponses and of these, 9 received injectable epinephrine.

Immunologic Assessments

Skin test wheal size increased from baseline in the peanut avoidance group. Children who were allergic to peanuts at 5 years had a pronounced increase in the size of the skin prick test wheal. These children also had higher specific IgE.

Peanut specific IgE did increase over time in both the avoidance group and in the peanut consuming group. However, in the peanut consuming group, there were fewer children who had very high peanut specific IgE levels.

Peanut specific IgG and IgG4 levels were higher in the peanut consuming group.

Discussion-

Among infants who have high risk atopic disease (severe eczema and/or egg allergy) continued peanut consumption starting in the first 11 months of life, compared to peanut avoidance, resulted in a significantly smaller proportion of children with peanut allergy at age 5 years. The reduction was 86% in those with negative peanut skin prick tests and 70% in those with positive peanut skin prick tests. The trial was safe, well tolerated, and effective.

The weaknesses of the study was the lack of a placebo group, however this is lessened by the utilization of the objective peanut challenge. This study did not include low-risk infants and it did not include infants with peanut skin prick test wheals that were large (4 mm). Another weakness was not collecting bedding dust earlier to validate consumption/exposure.

At age 5 years in the peanut avoidance group, the skin test size and the specific IgE to peanut was larger in the avoidance group. The peanut consuming children had early and high levels of peanut specific IgG and IgG4. In the avoidance group, unless specific IgE to peanut was high, an elevated IgG4 level was associated with the absence of an allergic reaction to peanut. IgG4 may be protective.

Very early sensitization to peanut was seen in this study in infants who had no history of peanut consumption. As noted in previous work, the sensitization may be coming from environmental exposures, whereas early oral exposure may lead to immune tolerance.

“Our findings showed that early, sustained consumption of peanut products was associated with a substantial and significant decrease in the development of peanut allergy in high-risk infants. Conversely, peanut avoidance was associated with a greater frequency of clinical peanut allergy than was peanut consumption, which raises the questions about the usefulness of deliberate avoidance of peanuts as a strategy to prevent allergy.”

Reviewers Comments

Wow!

There are so many thing to share about this paper. First the results apply to a specific population of children;

  1. The diagnostic tool for screening was the skin prick test NOT THE INFANT FOOD ALLERGYPANEL.
    1. The size in measured millimeters of the wheal response determined if the infant was in the study and in which group.
    2. If the skin test response to peanut was too large (>4mm) the child was excluded
    3. To comply with this protocol a skin prick test needs to be done.
    4. Contrary to popular belief, young children can be skin tested with reliability.
  2. The children had to have
    1. Severe eczema – there are scales to use to classify severity (SCORAD)
    2. Egg allergy – (defined as a positive test to egg and symptoms with exposure)
    3. One or both of the above

This is the population studied and the population to which the results can be extended.

Also note;

  1. IgG and IgG4- not a bad thing to have against peanut – in context it is related to protection.
  2. Food Challenges – need to be performed
  3. Context- depending where you look
    1. 1 peanut- 0.5 gram of protein
    2. 1 ounce- 7.3 grams
    3. 2 tablespoons of peanut butter- 8 grams of peanut protein
  4. Peanut source- Bamba a corn and peanut mixture.
  5. Peanut in bedding dust- surprised to see even 4 micrograms -? How common is this and does it explain those frustrating fleeting episodes of hives in the peanut sensitive children.

I had the pleasure of being in the audience during Dr. Lack’s presentation. He pointed out that timing is critical- 4-11 months of age. You would want to start this before the skin prick test wheal size becomes greater than 4 mm. He noted that in those infants who are sensitized to peanut the early exposure per this protocol may stop the progression of sensitization/allergy.

Dr. Lack was quoted as suggesting the involvement of a pediatric allergist for the skin prick testing and peanut challenge.

My hopes are that we will be seeing families who want to try this protocol. At Riley Hospital for Children we are set-up for food challenges. Dr. Vitalpur offers 4 food challenge opportunities every other Friday and my clinic at IU North has 8 food challenges per week- 2 on Wednesday and Thursday mornings and 2 on Wednesday and Thursday afternoons. Dr. Kloepfer can also help with food challenges. We would need an initial visit to go over the history, examination, and testing prior to scheduling a peanut challenge. We have experience and expertise in doing food challenges in children including the infants. We also have a significant support system available for children.

Frederick E. Leickly, MD, MPH 2/28/2015

February 28, 2015 · fleickly · No Comments
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Skin Prick Tests and Blood Tests for Allergy in Young Children

‘Disagreement between skin prick tests and specific IgE in young children’ by A.M Schoos, B.l.k. Chawes, N. Folsgaard, N. Samandari, K. Bonnelykke, and H. Bisgaard.

 This article appears as a pre-publication. It has been accepted by the journal ‘Allergy’. Of note, even as a pre-publication, it has been a very popular article. I presented this article at our section’s journal club today (November 4, 2014). What follows is somewhat lengthy synopsis and review of this article.

Purpose- to evaluate the agreement between skin prick tests (SPTs) and specific IgE (sIgE) results when diagnosing allergic sensitization. (Reviewers note- specific IgE is the blood test that is used for allergy- once upon a time it was referred to as RAST.)

Methods- The children were part of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). They were born to mothers who had asthma. The children were evalutated every six months for seven years. The evaluation for allergic sensitization was done by sIgE and SPT at 6 months, 18 months, 4 years, and 6 years. SPTs were done to milk, egg, wheat, soy, codfish, and peanut. The blood tests or sIgEs were performed for the same items that were used for the SPTs. At age 7 years the clinical history of food allergy and allergic rhinitis was obtained by a standardized interview (as opposed to a parental questionnaire).

The data was presented with prevalence curves, logistic regression, Kappa coefficients, and receiver operating characteristic curves. A Kappa value of 1.0 indicates perfect agreement between tests. The gradations below perfect were almost, substantial agreement, moderate, fair, slight, and poor strength of agreement between the two tests.

Results-

                Table 1-baseline characteristics of the population- there were 411 children enrolled of which 389 were tested and 22 were not. The table looked at gender, socioeconomic factors, early life exposure to cigarette smoke, and the allergic disposition of mother (who had to have asthma to qualify) and father. The only difference between those tested vs. not tested was income. Those children not tested were from families with lower incomes compared to those who were tested.

                Figure 1- Inhalant Allergens: Changes in prevalence over time.

 

  6 months 18 months 4 years 6 years
SPT 1.5% 3.8% 8.4% 15.4%
sIgE 0.6% 4.2% 18.1% 24.8%

 

This shows the age at which sensitization occurs and the impressive divergence between SPT and sIgE- the blood test results are almost twice the skin test results. The pollens (grass, birch, and mugwort) are seen first at age 4 years and mold sensitization was seen at age 6 years. The perennial allergens are seen starting at age 18 months. Note the few children who had allergic sensitization to inhalant allergens at ages 6 and 18 months.

                Table 2- Agreement of SPT and sIgE, these are the Kappa values. (Do the tests agree with each other?)

                6 months- -0.0011 Poor

                18 months- 0.48 Moderate

                4 years- 0.45 Moderate

                6 years- 0.55 Moderate

Note the scale- poor, slight, fair, moderate, substantial, and almost perfect. A 1.0 is perfect and the moderate range is 0.41 to 0.6.

                Figure 3- Food Allergens: Changes in prevalence over time

A note- cod was not included due to few positive results.

 

  6 months 18 months 4 years 6 years
SPT 5.3% 5.1% 3.7% 3.0%
sIgE 7.8% 12.1% 15.0% 18.9%

 

The number of SPT positive children declined from 6 months to 6 years for foods whereas the number of children positive by the blood test increased over the same interval.

                Table 2- Agreement of SPT and sIgE, these are the Kappa values.

                6 months- 0.46 Moderate

                18 months- 0.31 Fair

                4 years- 0.16 Slight

                6 years- 0.14 Slight

To repeat -Note the scale- poor, slight, fair, moderate, substantial, and almost perfect. A 1.0 is perfect and the moderate range is 0.41 to 0.6.

The next two tables do not appear in the paper. The reader is directed to an online repository for 4 more tables and 3 figures.

                Table E2- Clinical symptoms of inhalant allergy at 6 years of age and relation to sensitization.

Listed are the inhalants tested for; birch, grass, mugwort, horse, dog, cat, house dust mite, and molds. There were 266 of the children who had both SPT and sIgE performed at age 6 years.

Clinical Allergy (CA) 93
Total number with positive skin prick tests 78
Total number with positive blood tests 150
CA with no positive test 46
CA with both tests positive 26
CA with only a skin test positive 7
CA with only a blood test positive 14

Inhalant sensitization diagnosed by skin prick test compared to blood tests was better related to symptoms of nasal allergy: the positive predictive value (chance that the condition is present with a positive test) was 42.3% for the skin tests and 26.7% for the blood test. Note about half did not have any test positive.

 

Table E3- Clinical symptoms of food allergy at 6 years of age and relation to sensitization.

Listed are the foods tested for; wheat, egg, milk, soybean, cod, and peanut. There were 264 of the children who had both SPT and sIgE performed at age 6 years.

 

Clinical Allergy (CA) 12
Total number with positive skin prick tests 8
Total number with positive blood tests 75
CA with no positive test 6
CA with both tests positive 5
CA with only a skin test positive 0
CA with only a blood test positive 1

Skin prick test results for foods were better related to clinical symptoms than blood tests; the positive predictive value was 62.5% vs. 8.0% for the blood test, however half of the cases of clinical food allergy were not accompanied by a positive test.

Discussion- There is poor to moderate agreement between SPTs and sIgEs in diagnosing allergic sensitization in young children. This mismatching increases with age for foods. The choice of a test may have a major impact on results in research and guidance in clinical practice. Allergy testing should only be done in children with meaningful symptoms and not used as a screening tool.

Strengths of the Study- first evaluation of SPTs and sIgEs in a large birth cohort with the tests done simultaneously and frequently (4 times) over 6 years.

Weakness- no food challenges were performed. This was done in an at-risk population (mothers with asthma) not a general population.

The agreement of these two tests during the pre-school years was at best moderate, but a striking worsening of agreement was seen with foods as the child increased in age. The point prevalence for food sensitization diagnosed by SPT was in line with what we know about food allergy in children which will decrease with age. However the blood test for food antibodies increased with age. This suggests that this sIgE test does not reflect clinical food allergy.

Why does this happen? Extracts for skin testing may not contain all the components of foods- there may be more positive blood tests due to differences in what each contains. Cross-reactivity between foods and pollens may account for some of the difference, but that would not explain what was seen with milk where there were 35 sIgE positive children who did not have a positive SPT. The SPT and sIgE may measure different things- one is antibodies attached to mast cells in the skin while the other is found in the blood.

Warning- this may have an impact on research and clinical practice-

  1. Research- clarify the definition of sensitized vs. allergic children. The choice of test may select out different populations of sensitized children.
  2. Clinician- emphasize careful interpretation, base the diagnosis on the assessment method, the clinical history, the age of the child, and the type of allergy. Allergy testing should never be used indiscriminately for screening purposes.

Both tests had a low predictive value for clinical food allergy and symptoms of allergic rhinitis, with only 50% of the symptomatic children having a positive test.

There is substantial disagreement between SPT and sIgE for diagnosing allergic sensitization to common inhalant and food allergens in young children with increasing disagreement with age for foods. SPT and sIgE results cannot be used interchangeably.

The lack of agreement between tests and a poor correlation to clinical disease emphasizes the point that allergy testing should not be used as a screening tool in children.

Reviewers Comments

This is a very interesting, well done, and informative paper on a topic that has been the bane of pediatric allergy. Tests are done ‘just to see what the child is allergic to’ without a discriminating history of clinical conditions present in the child. Allergy tests are terrible for screening and this should not be done. The value of the test is dependent upon the story that supports what happens to the child with exposure. In allergy, the clinician uses the test to verify a clinical impression.

Note that the paper is very careful in stating that this is sensitization- meaning the making of an allergy antibody. Clearly, antibodies can be made and there may be absolutely no clinical reactivity. The allergic child has a history of an allergic reaction with an exposure and a positive test to that substance. Allergy is a story and a test whereas sensitization is only a test (which may never have a story to match it).

FEL 11-5-2014

November 6, 2014 · fleickly · No Comments
Tags: ,  · Posted in: Allergies, Allergy in Children, Allergy Testing, Interesting articles

Pollen Counts for Indianapolis – Final Report

The end of the pollen season- Frosts tend to wipe out the pollen. We have mold spores on the rods, but hardly any pollen.

October 31, 2014 weeds

 

 

 

 

 

 

October 31, 2014 ragweed

 

 

 

 

 

 

 

FEL 11-2-2014

November 2, 2014 · fleickly · No Comments
Posted in: Uncategorized

Indianapolis Monthly ‘Top Docs’ 2014

I had the honor of being named one of the ‘Top Docs’ in the November issue of Indianapolis Monthly. Under the heading of Pediatric Allergy there are two names my colleague Dr. Girish Viitalpur and myself.
This year they also asked to fill out a survey and one of my answers made it. The question was ‘How realistic is your favorite TV show about doctors?’ I was tempted to go with ‘Ben Casey’ but no one would have know about that one. ‘Man, Woman, Birth, Death, Infinity.

Indianapolis Monthly 'Top Docs' 2014 001

 

 

 

 

Indianapolis Monthly Top Doc 2014 2 001

 

 

 

 

Top Doc 2014 3 001

 

 

 

 

 

 

 

 

 

 

 

FEL 11-2-2014

November 2, 2014 · fleickly · No Comments
Posted in: Uncategorized

Indianapolis Pollen Counts for the week- October 13th through 17th, 2014

Interesting pollen week. Most of the counts were low or none. Today mold was the most common respiratory allergen seen. I am seeing a few grass pollens- they are unmistakable- very large spheres. Grass pollen is out of season, however I wonder if the ornamental grasses (we have a few in the yard) shed their pollen at different times? The numbers have not been more that 2-3 grains. I also saw one pine pollen- this is way out of season. Pine pollen is also very easy to identify under the microscope. All in all, the pollens are dwindling.
I also just finished my first full week of work (that would be 5 days) in the clinic/office. I was dragging by Thursday. Now I have the weekend to recover.

October 17, 2014  weeds

 

 

 

 

 

 

October 17, 2014 ragweed

 

 

 

 

 

 

 

FEL 10-17-2014

October 17, 2014 · fleickly · No Comments
Tags: , , , , , , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Ragweed, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Weed Pollen

Indianapolis Pollen Counts for Sunday October 12th, 2014

We had frost on the roof this morning, but that did not keep ragweed from making an appearance. The ragweed count was low at 2 and the total weed count was low at 4 with chenopods and ragweed contributing to that total.

October 12, 2014 weeds

 

 

 

 

 

 

October 12, 2014 ragweed

 

 

 

 

 

 

 

FEL 10-12-2014

October 12, 2014 · fleickly · No Comments
Tags: , , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Ragweed, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Weed Pollen

Weed Pollen Counts for Indianapolis – Saturday October 11th, 2014Only chenopod weeds out there today. The level was low at 2 grains of weed pollen per cubic meter of air sampled for the day.

Only chenopod weeds out there today. The level was low at 2 grains of weed pollen per cubic meter of air sampled for the day.

October 11, 2014 weeds

 

 

 

 

 

 

FEL 10-11-2014

October 11, 2014 · fleickly · No Comments
Tags: , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Weed Pollen

No Pollens to Report for Indianapolis Today- October 10th, 2014

Absolutely no pollens on the rods today.  Could the season be over?

FEL 10-10-2014

October 10, 2014 · fleickly · No Comments
Tags: , , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Ragweed, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Uncategorized, Weed Pollen

Indianapolis Pollen Count for Thursday October 9th, 2014- 1 weed pollen- thats all!

No ragweed today- just one miserable wet chenopod weed pollen per cubic meter of air sampled. That would be a low count for weeds.

October 9, 2014

 

 

 

 

 

 

FEL 101-9-2014

October 9, 2014 · fleickly · No Comments
Tags: , , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Ragweed, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Weed Pollen

Indianapolis Pollen Counts for Wednesday October 8th, 2014

First day back to work since August 28th. It was great to see everyone. Moving around was tenuous. I had to stand or sit on the exam table to do my interviews, that wheeled stool by the desk just looked a bit too risky. I ventured into a half-day session which went well. I have this habit of not leaving the office until everything is done. So I took care of every message, dictated charts and letters, and signed off on dictations. I am up to date. Tomorrow is my first full day-lets see how it goes.
Today’s pollen counts were meager- a strong ‘1’ for ragweed and a low ‘3’ for the chenopod weed pollens.

October 8, 2014

 

 

 

 

 

 

October 8, 2014 ragweed

 

 

 

 

 

 

 

FEL 10-8-2014

October 8, 2014 · fleickly · No Comments
Tags: , , , ,  · Posted in: Pollen Counting, Pollen Counting- Indianapolis, Ragweed, Seasonal Allergies, Seasonal Allergies-Pollen Counts, Weed Pollen