Epi-Pens are a common sight today as peanut allergies, once rare, have become more common.

Peanut allergies, once rare, have become much more common. The Epi-Pen is used to treat  life-threatening anaphylactic reactions.

Severe food allergies, in particular peanut allergies, have become a significant public health issue. Peanut butter sandwiches, once a staple of school lunches, are disappearing as schools and daycares are declared “nut-free zones”. Children today are forbidden from sharing food at school. All of this is in reaction to the growing numbers of children with severe, life-threatening allergies to peanuts. The American prevalence has grown from an estimated 0.4% of children and 0.7% of adults in 1999, to approximately 2% among children in 2010. While anaphylactic (life-threatening) allergies can occur to other food products, peanut allergy is the leading cause of food-related anaphylactic death, and its growing prevalence has driven considerable research into its causes. New parents are anxious to prevent peanut allergies in their children if possible, so there have been persistent questions about whether peanut allergies were preventable, either by modifying the diet of the mother or the infant. There’s been a lack of good science to answer this question – until now.

Searching for the cause of life-threatening allergies

Allergies are a product of our immune systems, with multiple biochemical pathways triggered in response to a specific antigen. “Allergy” can cause reactions that range from mild to potentially fatal. Most food-related allergic reactions are not life-threatening. Anaphylaxis is the term that describes a rapid and severe immune response, which can occur in response to a drug (the most common cause of anaphylaxis), an insect, or food. Eight foods cause over 90% of anaphylactic reactions: milk, eggs, peanuts, tree nuts, fish, shellfish, soy, and wheat. Reactions may involve multiple body systems (gastrointestinal, skin, respiratory) including breathing difficulties and swelling of the throat. Fatal reactions are thankfully rare, particularly if they’re treated promptly with epinephrine (sold for consumer use as the Epi-Pen.) Death occurs due to upper airway obstruction, vascular fluid shifts, and depressed heart function. The risk of anaphylaxis, and how quickly it can appear in any individual with a history of allergy, is difficult to predict, and can be influenced by age, the type of allergen, the extent of exposure, and underlying illnesses, like asthma.

Some anaphylactic food allergies (e.g., milk and egg), can resolve over time. Tree nut and peanut allergies, however, are more likely to be life-long conditions. The price of life is eternal vigilance. Every food, every bit, forever. Desensitization trials look promising but we’re not there yet. The only proven way to prevent reactions in those with a history of anaphylactic allergies is strict and complete avoidance of the allergen.

The evolution of the guidelines

In the absence of knowing what’s causing anaphylactic allergies, guidance from health professionals has been mainly empirical, seemingly based more on professional experience than data. The oldest specific guidance seems to date back to 2000. Here’s the American Academy of Pediatrics guidance on hypoallergenic infant formulas. It notes:

Elimination of cow’s milk, eggs, fish, peanuts and tree nuts, and other foods from the maternal diet may lead to resolution of allergic symptoms in the nursing infant.

There is no reference given for this statement. The guideline includes the following recommendation:

Conclusive studies are not yet available to permit definitive recommendations. However, the following recommendations seem reasonable at this time:

a)  Breastfeeding mothers should continue breastfeeding for the first year of life or longer. During this time, for infants at risk, hypoallergenic formulas can be used to supplement breastfeeding. Mothers should eliminate peanuts and tree nuts (eg, almonds, walnuts, etc) and consider eliminating eggs, cow’s milk, fish, and perhaps other foods from their diets while nursing. Solid foods should not be introduced into the diet of high-risk infants until 6 months of age, with dairy products delayed until 1 year, eggs until 2 years, and peanuts, nuts, and fish until 3 years of age.

b)  No maternal dietary restrictions during pregnancy are necessary with the possible exception of excluding peanuts;

Again, no citations are given as recommendations were entirely empirical – that is, based on expert opinion. It’s possible these recommendations were followed by thousands, if not hundreds of thousands women through the 2000s. And all this time, the prevalence of nut allergies continue to climb.

In 2008, because of evolving evidence, the”American Academy of Pediatrics recommendations on the Effects of Early Nutritional Interventions on the Development of Atopic Disease“, were updated. There was now much more data, much of it equivocal, and the guideline’s authors were far more circumspect with respect to what the appropriate approach was. The biggest change was the elimination of recommendation for pregnant women to restrict their diet. And there was no longer a recommendation to avoid potential allergens after about 4-6 months:

  1. Although solid foods should not be introduced before 4 to 6 months of age, there is no current convincing evidence that delaying their introduction beyond this period has a significant protective effect on the development of atopic disease regardless of whether infants are fed cow milk protein formula or human milk. This includes delaying the introduction of foods that are considered to be highly allergic, such as fish, eggs, and foods containing peanut protein.
  2. For infants after 4 to 6 months of age, there are insufficient data to support a protective effect of any dietary intervention for the development of atopic disease.
  3. Additional studies are needed to document the long term effect of dietary interventions in infancy to prevent atopic disease, especially in children older than 4 years and in adults.

There was a lack of evidence to show that avoiding potential allergens was advisable, but there was an open question about whether either exposure or avoidance could reduce the appearance of allergies. Happily, there was an excellent clinical trial published in 2015 that provides definitive proof that avoidance was worsening the problem.

The study that overturned the consensus

The Learning Early About Peanut (LEAP) study, published in 2015 in The New England Journal of Medicine, was the definitive trial that proved that old approaches to preventing allergies were wrong. The investigators’ question was formed out of an observation: The risk of peanut allergy among Jewish children in the United Kingdom was 10x as high than Israeli children with similar ancestry. It was noted that while peanuts were generally withheld in the first year of life in the United Kingdom, they tended to be introduced at around 7 months in Israel. The investigators’ hypothesis was that early introduction of peanut protein into the diet might reduce the risk of peanut allergy.

This was a randomized, open-label study of 640 children in the United Kingdom. To be eligible to participate, children had to be 4 months to 11 months of age, and had severe eczema, egg allergy or both. The average age at screening was 8 months. All children received skin tests for peanut allergy and were then randomly assigned to dietary peanut consumption or avoidance. Children randomized to peanut consumption received 6 grams of peanut protein per week until 60 months of age. The peanut product used was an Israeli product called Bamba. (Wikipedia tells me this product makes up 25% of the Israeli snack market).

The primary outcome was the prevalence of peanut allergy at 60 months of age. Of the 530 infants who initially had negative skin tests and were analyzed at 60 months, peanut consumption had a dramatic effect: The rate of peanut allergy was 13.7% in the “avoidance” group and 1.9% in the “peanut consumption” group. This is an 86% relative reduction in the prevalence of peanut allergy.

Peanut consumption was beneficial even in children who had positive results on their initial skin test. At 60 months, the prevalence was 35.3% vs. 10.6% in the peanut consumption group, which is an impressive 70% relative risk reduction.

What this study showed was that peanut consumption at an early age could reduce the prevalence of peanut allergy in children, whether they were sensitized (secondary prevention) or not (primary prevention.)

The new guidance

A few weeks ago, the National Institute of Allergy and Infectious Disease (NIAID) issued addendum guidelines for the prevention of peanut allergy. The NIAID worked with 25 professional organizations, federal agencies and patient advocacy organizations to develop this new guidance. These guidelines incorporate the findings of the LEAP study and summarize the best evidence in making recommendations. There are actually three specific guidelines for infants at different risk levels. I am not going to review them in detail, as they’re all online, including specific guidance for parents, which I have excerpted below:

Guideline 1 recommends that if your infant has severe eczema, egg allergy, or both (conditions that increase the risk of peanut allergy), he or she should have peanut-containing foods introduced into the diet as early as 4 to 6 months of age [but only in conjunction with an evaluation by an Allergist]. This will reduce the risk of developing peanut allergy.

Guideline 2 suggests that if your infant has mild to moderate eczema, he or she may have peanut-containing foods introduced into the diet around 6 months of age to reduce the risk of developing peanut allergy. However, this should be done with your family’s dietary preferences in mind. If peanut-containing foods are not a regular part of your family’s diet (and your infant does not have severe eczema, egg allergy, or both), do not feel compelled to introduce peanut at such an early stage.

Guideline 3 suggests that if your infant has no eczema or any food allergy, you can freely introduce peanut-containing foods into his or her diet. This can be done at home in an age-appropriate manner together with other solid foods, keeping in mind your family’s dietary routines and preferences as described in Guideline 2.

The new guidance is summarized in Table 1 of the guideline:

Table 1 - NIAD panel on peanut allergy

Click to embiggen.

Oops

In a period of 15 years, there’s effectively been a 180° change in dietary advice, from peanut avoidance to early introduction of peanuts. It’s something akin to a “medical reversal”, a term coined by Vinay Prasad and Adam Cifu:

Medical reversal occurs when a new clinical trial — superior to predecessors by virtue of better controls, design, size, or endpoints — contradicts current clinical practice.

Prasad and colleagues have identified 146 medical practices that were ultimately contradicted. While this research studied new medical practices, not dietary guidelines, it highlighted that better controlled studies often contradict preliminary conclusions and medical practices, when treatment decisions are made based on low quality evidence. It’s a phenomenon that’s also been described, with respect to clinical trials, by John Ioannidis:

Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes. The extent to which high citations may provoke contradictions and vice versa needs more study. Controversies are most common with highly cited nonrandomized studies, but even the most highly cited randomized trials may be challenged and refuted over time, especially small ones.

Ioannidis, Prasad and Cifu highlight the reproducibility problems in the medical literature. While it is a reality that there will always be a baseline rate of reversal in medicine, owing only to statistical probability, there are a number of factors that make reversals far more common than necessary. The primary cause of medical reversal is obviously the quality of the evidence that informs any new health intervention. As evidentiary standards are lowered, the likelihood that any conclusion is wrong will grow, and the risk of subsequent reversal climb. While Prasad and Cifu outline other factors that can lead to eventual reversal, we don’t need to go much further than the evidence base itself when we examine peanut allergy guidance. The 2000 guidelines were based on expert opinion, not high quality evidence. While they may have sounded cautious and appeared reasonable, they were ultimately wrong. And it’s hard to deny that we have a greater prevalence of peanut allergies today as a result.

But the peanut avoidance guidance was also distinct from other types of medical reversals. This was not the adoption of a new test, treatment or technology, but a decision about dietary timing. There was a lack of good evidence, but guidance was offered nevertheless. Would we have been better off without any advice from the AAP? There’s a case to be made for withholding any guidance unless it’s based on the best evidence. There was no data to support any specific dietary advice. Ultimately the AAP felt it needed to offer advice. It was wrong.

Learning from this reversal

A high-quality clinical trial has led to updated guidance on how to minimize the risk of developing peanut allergies. This new evidence contradicts old guidelines, which were based entirely on expert opinion. There is now good data to show that the introduction of peanuts at an early age to select children will decrease the risk of developing an anaphylactic allergy. Given the impact of this guidance, it is essential that these findings be widely disseminated. Unfortunately we cannot turn back the clock and reverse the allergies that have emerged, some a likely consequence of well-intentioned, but wrong, advice. We can only study these decisions as we develop our advice today, with the intention of trying to be “less wrong” in the future.

Photos via flickr users MartinL and Vu Nguyen used under a CC licence.

Posted by Scott Gavura

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