Food allergies are a growing public health concern, according to the CDC, affecting approximately 5% of children in the United States and more than 50 million Americans overall.
Ninety percent of serious allergic reactions in the U.S. are caused by eight food groups, including milk, eggs, fish, crustacean shellfish, wheat, soy, peanuts and tree nuts.
There is no true cure for food allergies, only management plans, which can be tedious and invasive for both physicians and patients to establish and implement due to the individualized nature of food allergies.
“Everyone has a different story,” Princess U. Ogbogu, MD, section chief of allergy and immunology at The Ohio State University Wexler Medical Center, told Infectious Diseases in Children. “Because the immune system is very complex, care tends to be individualized to the patient’s genetic background and other surrounding circumstances, including what resources and availability parents have in terms of managing their child’s food allergy.”
Identifying problem foods can be difficult, especially as children get older and their diet encompasses more foods. Once problem foods are identified, management plans commonly consist of diet restriction that requires the child to avoid the problem food. Diet restriction is not always easy, however, as it can require lifestyle changes that may be difficult for children and parents to maintain.
These challenges have made food allergy a focal point of pediatric research, with studies like the Learning Early about Peanut Allergy (LEAP) trial is attempting to address the ambiguities behind allergy manifestation and prevention.
Jonathan E. Markowitz, MD, MSCE, of the Greenville Health System, said the process of dietary elimination for food allergies can be lengthy, tedious and expensive with repeated trial and error.
Photo courtesy of Alan Francis, Greenville Health System
Escalating incidence of food allergy
“Food allergy rates have been increasing,” Irene J. Mikhail, MD, an assistant professor of pediatrics at Nationwide Children’s Hospital, said in an interview with Infectious Diseases in Children. “Over the last several decades we have seen a rise in incidence of food allergy, mainly in Western, developed countries.”
Prevalence of peanut allergy alone has doubled in the past 10 years among children in Western countries, according to study findings published in the New England Journal of Medicine.
There are several theories as to why food allergy rates have been increasing, according to Mikhail.
For example, the “hygiene hypothesis” postulates that the decreasing incidence of infections in industrialized countries — due to improved hygienic practices and subsequent decreased microbial exposure — has contributed to the increasing frequency of autoimmune and allergic diseases. The theory asserts that the lack of exposure to micro-organisms has led to deficiencies in the development of the immune system and increased susceptibility to allergic diseases.
“Essentially, this theory says that we have become ‘too clean’ as a society, and our immune system does not know how to respond to that,” Mikhail said.
Data that support the hygiene hypothesis indicate that children with older siblings, who are likely to bring organisms or dirt into the home, have a lower rate of food allergy vs. eldest siblings or only children.
A subsequent theory suggests that the microbiome plays a significant role in development of food allergy. Early exposure, as early as in utero or during delivery, can alter organisms in the gastrointestinal system, which then can affect the development of food allergy.
A third theory, which is somewhat addressed by the LEAP study, proposes that the development of food allergy is affected by when and how the body encounters an antigen.
“Some believe that if the antigen is encountered early on via nonoral exposures this might predispose the patient to allergies vs. if the antigen is encountered early on orally, which may protect against food allergy,” Mikhail said.
Performed in collaboration between the Immune Tolerance Network and researchers at King’s College London, and conducted at Guy’s and St. Thomas’ hospitals, the LEAP study assessed whether early introduction of dietary peanut was an effective primary or secondary strategy for the prevention of peanut allergy.
Researchers randomly assigned 640 infants with severe eczema, egg allergy or both to consume or avoid peanuts until the age of 60 months. Study participants were aged 4 to 11 months at randomization.
At age 60 months, 13.7% of participants in the avoidance group exhibited peanut allergy, compared with 1.9% among participants in the consumption group (P < .001), according to data for 530 children.
Among 98 children who initially had positive skin-prick test results for sensitivity to peanut, 35.3% of those randomly assigned to avoidance had peanut allergy at 60 months vs. 10.6% of those assigned to consumption (P = .004).
“Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody,” study researcher George Du Toit, MB, BCh, of King’s College London, and colleagues wrote in the New England Journal of Medicine.
Clinical implications of the LEAP study
The LEAP study findings will likely have a significant impact on clinical practice, as they suggest that previous recommendations from the AAP, which stated that children should not be exposed to allergenic foods until an older age, were incorrect. However, the recommendation was revisited and retracted in 2008, as the academy did not have significant data supporting the recommendation.
“We basically said, as a scientific community, we do not have enough data to support one recommendation over another,” Mikhail said. “Currently, there is no guideline for when to expose children to allergenic foods.”
The LEAP study is one of the first studies to provide significant evidence that the earlier the immune system is exposed to an allergen, the more protective it is against developing food allergy.
“Clinically, I believe we will see more parents introducing potentially allergenic foods to their children at an earlier age,” Mikhail said. “This is not without risk. It is important to look at the LEAP study and understand what the study was designed to do; the questions the study answered.”
Ogbogu echoed this sentiment. The LEAP study examined early introduction of peanut among a specific group of infants with eczema or egg allergy, she says; therefore, the study findings may be safely applied only to children who fall within this category.
Nevertheless, physicians agree the LEAP study will spur much needed discussion on when to introduce potentially allergenic foods into the diet and prompt new guidelines to address the issue.
“The study findings are interesting in that they affect both primary and secondary prevention of food allergy,” Ogbogu said. “Primary prevention meaning preventing children who are at risk for developing food allergy from developing it. Secondary prevention meaning modifying the immune system of children who have already been sensitized to the food allergen so they do not go on to manifest it. That is groundbreaking in terms of how we would approach this in the clinic now.”
An ongoing trial, called LEAP ALONG, is being conducted as a follow-up to the LEAP study that will address subsequent questions, according to study researcher Peter H. Sayre, MD, PhD, chief medical officer of the Immune Tolerance Network at the University of California, San Francisco.
“There is a future story to be told because the question will be asked — and is being asked — how long should children remain exposed to peanut in order to remain tolerant?” Sayre told Infectious Diseases in Children. “We hope that question will be answered by LEAP ALONG, which asks all study participants from the original LEAP study not to consume peanut for a year — both children who have been eating peanuts and those who were previously avoiding peanuts. We hope to report on this trial a year from now.”
Clarifying eosinophilic esophagitis
In some patients, food allergy manifests as eosinophilic esophagitis (EoE), a chronic condition that is increasing in prevalence and recognition, but is often mistaken for gastroesophageal reflux, as they have similar presentations.
“At the most basic level, EoE is allergic or inflammatory cells in the esophagus. As a physician, we worry about these cells because, if they remain in the esophagus they can lead to scarring and cause numerous complications in the long term,” according to Mikhail.
Although food allergy is the root cause of EoE, the condition does not present like traditional food allergies. It does not usually involve an anaphylactic reaction with wheezing, hives or changes in blood pressure. Rather, symptoms of EoE vary across age groups, but typically patients have difficulty swallowing, as the esophagus can become so narrow that food may become stuck.
There are two treatment approaches for EoE, dietary elimination and medication. The former involves identifying the problem food and then eliminating it from the diet. While this tactic addresses the crux of the problem, it is not an ideal solution. Dietary elimination can require trial and error to figure out what foods are causing disease. Further, the only way to definitively know if the correct food has been identified is to conduct an endoscopy, which can be invasive and expensive.
Peter H. Sayre
“The process of dietary elimination can be very lengthy, with repeated trial and error of removing foods and conducting another endoscopy to see if inflammation has improved and if not, changing the diet again and repeating the entire process. It can be tedious, lengthy and expensive,” Jonathan E. Markowitz, MD, MSCE, division chief of pediatric gastroenterology, Greenville Health System, said in an interview.
Due to this inconvenience, some patients choose instead to treat EoE with medication that coats the esophagus and reduces inflammation at the surface. This option is especially attractive to older patients whose diet is so complex that identifying the problem food is nearly impossible and for those who do not wish to commit to eliminating the problem food.
Nevertheless, Markowitz noted, medication does not target the root of the problem.
Hardships and looking to the future
“The hardest thing for me is when I recommend a diet, I want it to be a diet with the highest chance of efficacy, but I do not want that diet to be very restricted,” Mikhail said. “Trying to find a balance between the least restrictive and most effective diet can be tricky.”
Markowitz also mentioned this difficulty, explaining that the complexity and individuality of food allergy and EoE can make it challenging to identify problem foods. Even the best allergy tests only correctly identify allergies in approximately 60% to 70% of patients, he said.
“Our allergy testing has not caught up with the complexity of EoE,” according to Ogbogu. “Current testing looks at antibody reaction, but there may be other immune factors that play a role in development of EoE.”
On the other hand, while medication can be an easier fix for EoE, there are no medical treatments for EoE approved by the FDA.
“Everything we do to treat the disease beyond diet is considered ‘off-label,’ using medication in ways they were not designed or tested for,” Markowitz told Infectious Diseases in Children. “Fortunately, there is enough published evidence that indicates using these medications for treatment of EoE is safe and that the side effects are relatively minimal.”
It can be difficult, however, to be reimbursed by insurance companies for using off-label medications, Markowitz noted, which creates additional complications.
Fortunately, the future of food allergy and EoE is promising. The complexities and mysteries behind these conditions drive research and development to find answers.
“About 7 years ago, eliminating the top six foods was a popular dietary restriction method. Now, physicians are experimenting with less restrictive diets, for example, just removing milk and wheat from the diet. We are learning that a proportion of patients respond to those methods without necessarily having to undergo allergy testing or more extensive eliminations,” Markowitz said.
Mikhail said she has been suggesting milk avoidance more frequently in her practice based on data that shows milk tends to be a common cause of EoE.
Furthermore, endoscopies may not be necessary to test for EoE in the future, as research is being conducted to find different methods of retrieving tissue samples.
“New technologies are in trial right now using things like strings or capsules the patient can swallow from which the physician can get samples of biologic material,” Markowitz said. “Hopefully they can acquire enough of a sample to detect whether the disease is active without doing an endoscopy.”
Genetics also may play a role in diagnosing EoE in the future, as physicians continue to learn about what genes suggest about patient risk.
“More and more genes have been identified that can indicate the patient’s risk for EoE. Ultimately, we hope these genes will give us insight into why this disease occurs and potentially better ways of preventing or treating disease once it develops. Though, making the leap from knowing the gene to being able to prevent disease is still a long way away,” Markowitz said.
Managing food allergies at school
In the meantime, management of food allergies must depend on resources currently available, which requires efforts from all corners of society.
Even after problem foods are identified, it may be difficult for patients to avoid those foods successfully. This can be especially difficult for young children who attend day care or school; without supervision a young child may accidentally ingest the allergenic food.
The key to successful management of food allergy among children is awareness, the researchers say. The patient and parent will likely receive education from their physician on how to avoid problem foods and identify an allergic reaction, but most children spend the majority of their day at school. Therefore, teachers and aides also should be educated about food allergies.
“The best way to handle food allergies at school begins with awareness,” Gary S. Rachelefsky, MD, a professor of pediatric immunology, allergy and rheumatology at the University of California, Los Angeles, and an Infectious Diseases in Children editorial board member, said in an interview. “The pediatrician or PCP should include a food allergy action plan in the patient’s medical records and the teacher, aide, cafeteria staff and school nurse should be made aware of what children are at risk for severe reaction.”
Instead of isolating children with food allergies, which can cause significant psychosocial adverse effects, Rachelefsky recommends that schools practice awareness and supervise children to ensure they safely avoid problem foods.
Further, school staff should be educated on how to identify an allergic reaction, he said. This can be achieved through lectures given by the school nurse or a physician about food allergy, how to recognize a reaction and how to handle children with food allergies.
“The key is education,” Rachelefsky said. – by Amanda Oldt
Du Toit G, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1414850.
For more information:
Jonathan E. Markowitz, MD, MSCE, can be reached at 200 Patewood Drive, Suite A140, Greenville, SC 29615.
Irene J. Mikhail, MD, can be reached at 700 Children’s Drive, Columbus, OH 43205.
Princess U. Ogbogu, MD, can be reached at 473 W. 12th Avenue, Columbus, OH 43210.
Gary S. Rachelefsky, MD, can be reached at 1131 Wilshire Boulevard, #202, Santa Monica, CA 90401.
Peter H. Sayre, MD, PhD, can be reached at 400 Parnassus Avenue, 4th Floor, San Francisco, CA 94143.
Disclosures: Markowitz, Mikhail, Ogbogu, Rachelefsky and Sayre report no relevant financial disclosures.
Should EoE be managed with dietary restriction or medication?
Dietary restriction is the best way to manage EoE.
We have gained a better understanding of eosinophilic esophagitis (EoE) over the past decade. Current guidelines define EoE as a “chronic immune/antigen-mediated” esophageal disease. Advances in allergy have helped us to understand that food allergy can be IgE-mediated, non-IgE mediated or as in the case of EoE, a combination of both. This may help to explain the variation in both the clinical presentation and specific triggers of this disease.
Current treatment options for EoE include the use of corticosteroids and food elimination. While studies demonstrate the efficacy of topical steroids, their long-term safety is unknown, they are not FDA approved nor effective in all patients. It should come as no surprise that parents of young children struggle with this option given that EoE is a chronic disease and recurrence is inevitable when topical steroids are discontinued.
Although symptoms of esophageal dysfunction in EoE vary according to age, food antigen mediated eosinophilic inflammation is the root cause in most patients. Elemental diets are the most effective treatment in EoE, demonstrating efficacy in over 90% of patients according to a recent meta-analysis, supporting food allergy as the major culprit in EoE.
Elemental diets are not practical in most patients. An empiric six food elimination diet (SFED) or food elimination based on allergy testing are also effective. An SFED was effective in 72% of patients based on a meta-analysis of diet therapy in patients with EoE. Food elimination prevents esophageal inflammation and should be considered as initial therapy. The long-term goal is not a highly restrictive diet, but rather a process of identifying triggers through reintroduction of foods once symptom control and histological remission are obtained. Collaboration between allergists, gastroenterologists and registered dietitians can help patients expand their diet, find allergen-free food alternatives, ensure adequate nutrition, and provide long-term disease management without medications.
Douglas Johnston, DO, is an allergist/immunologist at Asthma & Allergy Specialists in Charlotte, NC. He can be reached at 8045 Providence Road, Suite 300, Charlotte, NC 28277. Disclosure: Johnston reports financial ties with Abbott Laboratories and Nutricia.
Medication is a safe and effective way to manage EoE.
Medication has been a management method for EoE for more than 15 years. The typical medication consists of topical swallowed steroids, although systemic steroids can be used in select cases. These medications have been studied and have been proven to be safe and efficacious in improving clinical symptoms and resolving tissue disease in the majority of patients.
Although diet is, by far, the most likely cause of EoE, dietary restriction is not always the best therapeutic option for all patients. Sometimes a patient has issues with so many foods that going on a diet to avoid those foods is not only difficult for the patient but also for the family and physician. Severe restricted diets may cause poor nutrition unless the patient is provided a supplemental formula, which, for some people can be both expensive and unpalatable.
Further, it is not always easy to discover causative foods and many physicians do not have easy access to additional personnel (nurses, dieticians), who are often essential to ensure proper implementation and success of dietary therapy. Because of these issues medication is often a more viable option. It is often easier to institute dietary therapy for children as they spend more time at home with parents who can more easily control their dietary choices, while adolescents and teens may feel that dietary restriction is burdensome. The same can be said for many adults. It is very difficult for people to make a life-long dietary change when a medical therapy exists.
Another example involves people who have been on a very restrictive diet for many years. Some children must be placed on a strict amino-acid based formula because of the severity of their food reactions. Many of these patients require enteral tube feeding. Moreover, there are many adolescents or adults who have been on a restricted diet for years. Often, these individuals become non-compliant with their diet, thus, a change to medical therapy is more feasible. For many patients it is easier to take a pill once a day than maintain a diet.
Finally, a few individuals present with severe dysphagia, weight loss and esophageal narrowing from fibrosis. In these cases, oral steroids, such as prednisone, are useful when used as an initial therapy for a short period of time. Following oral steroids therapy, the patient can then begin either dietary therapy or topical steroids. Ultimately, it is of utmost importance to discuss all of the therapeutic possibilities with patients and families. The best management of EoE is a give and take between the physician and the patient in order to help the patient and family understand the pros and cons of each therapy so that they can decide on the best therapeutic option.
Chris A. Liacouras, MD, is a pediatric gastroenterologist in the division of gastroenterology, hepatology and nutrition at the Children’s Hospital of Philadelphia. He can be reached at 34th Street and Civic Center Blvd, Philadelphia, PA 19104. Disclosure: Liacouras reports financial ties with Abbott Nutrition and Nutricia.