Emerging Food Allergy Revolution

Kathryn Smith, DO I kathryn.marie.smith@gmail.com

AUTHOR DISCLOSURES:

No relevant financial affiliations.

INTRODUCTION

Food allergies are currently a popular topic in today's society, especially among families with young children and the medical professionals that care for them. It is not, however, a topic that has been thoroughly studied with a clear consensus on prevention or treatment. The purpose of this review is to highlight the current trends in diagnosis, prevention and treatment of food allergies in a society where food allergies are a trending topic.

The National Institute of Allergy and Infectious Diseases (NIAID) defines a food allergy as "an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food."1 Food allergies have been of great concern in recent years as studies have suggested that the prevalence of food allergies has been increasing over time.2 The current prevalence of food allergies in the US is suggested to be anywhere between 4-10%, with the most common childhood food allergies to cows milk, peanuts and shellfish.3•5 The prevalence of food allergies in other developed countries is similar to that of the US, with the most common food allergies in Canada being cows milk, peanuts and tree nuts, and Europe being cows milk, wheat and egg.3-4 While prevalence of all of these food allergies has increased over the last twenty years, it is unknown whether this is due to an actual increase in the number of allergies or an artificial increase due to increased awareness and reporting of food allergies.2

A multitude of risk factors have been proposed to lead to increased food allergies or food sensitization. Risk factors identified include sex, genetics, race/ethnicity, obesity, atopy, dietary fat, vitamin D insufficiency, antacid use, antioxidant consumption, hygiene, timing of exposure to foods, and route of exposure to foods (Table 1).6 Studies have shown that early oral introduction of commonly allergenic foods may lead to the prevention of allergy and that cutaneous exposure may lead to increased hypersensitivity.6•7 Genetic factors have not been widely studied, however, it has been seen that a family history of atopy or food allergies in immediate family members leads to an increased risk of developing a food allergy. This increased risk can be up to 80% when there are two immediate family members with allergies, compared with children without allergies in immediate family members.3•8 It has also been proposed that genetic mutations in the filaggrin gene lead to decreased barrier function in the epithelial lining of the intestine and thuslead to increased allergen sensitization.9·8

FOOD ALLERGY MECHANISMS

Food allergens are the proteins or chemical haptens found within different foods that the body's allergen-specific immune cells recognize and trigger an immunologic response.' These are the result of a typeI hypersensitivityreaction, which is an lgEmediated reaction between lgE and mast cells (Figure 1).10 Examples of physical findings associated with lgE mediated responses include urticaria, angioedema, bronchospasm, rhinitis, laryngospasm, diarrhea/vomiting, anaphylaxis, and oral allergy." Responses of this type typically occur within 30-60 minutes of exposure to the allergen.12

TABLE1: FIGURE 2:

 

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Anaphylaxis is the most severe form of this type of reaction and typically occurs within one hour of exposure. Symptomsgenerally beginning within 5-30 minutes of exposure, but may not develop for several hours. A biphasic reaction can also occur, where a second acute anaphylactic reaction occurs several hours after the first reaction in the absence of further exposure to the allergen. The second phase of the biphasic reaction typically occurs within eight hours of the first phase but can occur anywhere up to 72 hours after initial exposure. Symptoms of anaphylaxis include periorbital swelling/erythema, angioedema, wheezing, chest tightness, throat constriction, difficulty breathing, stridor, tachycardia, vomiting, headache, and feeling of impending doom (Figure 2).14 Fatal anaphylaxis from food allergies is rare, with approximately a 0.03-0.3 deaths per one million people annually in the general population and an approximately 1% death rate for all cases coded asfood anaphylaxis, with the most common cause of death being delayed epinephrine use.15

lgE mediated responses are the most common type of food allergy. In addition, there are non-lgE-mediated gastrointestinal food allergies (type IV hypersensitivity) as well as mixed lgE and non-lgE mediated food allergies.'·1112•17 The non-lgE mediated responses include food protein induced enterocolitis syndrome, food protein induced enteropathies, celiac disease, and the mixed responses include cows milk protein allergy, eosinophillic esophagitis, and eosinophilic gastroenteritis.11,12.17

A variety of other reactions to foods exist aside from traditional

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labeled as allergies when in fact the patient is not having a true allergic reaction. A food intolerance is a response that does not involve the immune system. Pharmacologic responses such as to caffeine or tyramine, enzyme deficiencies such as lactase, and non-specific gut and non-gut reactions to food such as irritable bowel syndrome, are all examples of food intolerances which have all been mistaken as food allergies."

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DIAGNOSIS OF FOOD ALLERGIES

Currently, there are no set criteria for the diagnosis of food allergies.2 As in all areas of medicine, the first step in diagnosis is taking a good, detailed history. The history should be able to tease out the cause of the food reaction and determine whether it is likely lgE mediated versus another type of reaction such as celiac disease, lactose intolerance, food-protein induced enterocolitis syndrome, or any of the other food reactions mentioned previously.7 Answers to questions such as "what happened?'' should help the clinician to discern allergy versus one of the other above mentioned reactions as they will present with different symptoms. The history is also key in directing the testing of the allergen and any likely cross-reactive foods.11 The history should include asking about and providing food labels, lists of ingredients of foods that have caused reactions, and/or a dietarylog in order to discern what may be the potential allergen.7

Once it has been decided that a food allergy is present, diagnostic tests are used in order to determine sensitization to the allergen. Common tests used are skin prick tests, atopy patch testing, measuring antigen-specific lgE (slgE), and the open food challenge.7•11

It is important to be aware that most of these tests are sensitive but not specific, meaning that there is a high probability of false positives." Primary care physicians can perform basic lgE testing and skin prick testing if resources allow, but any further testing should be conducted by an allergist.'"

Skin prick testing is common, quick and inexpensive. It consists of placing a small amount of allergen beneath the skin. This forms a wheal, whose diameter is then compared to both a positive and negative control. The positive control is histamine, as the allergic reaction is the result of histamine release from mast cells.7 Atopy patch testing, on the other hand, consists of applying food extract to the patient's back and watching for erythema, infiltration and papules after a period of 48-72 hours. This method is not used for lgE-mediated food allergies, but can be used for identifying delayed hypersensitivity reactions.11

SlgE tests are performed by taking the patient's serum and using an assay to incubateit withsurface-fixed allergens. SlgE antibodies found in the patient's blood will befound and identified by binding to labeled anti-lgE. The amount of slgE found in the patient's blood directly correlates with the likelihood of the patient having a clinically significant allergic reaction to the specific food allergen. The amount of slgE does not, however, correlate with the severity of the reaction.7 SlgE is helpful when positive with a history positive for lgE-mediated allergy, but is not helpful in ruling out allergy when history is positive or when ruling in allergy with a positive history and negative test.11

The gold standard test for diagnosing food allergies remains the double-blinded placebo-controlled food challenge. This challenge consists of ingesting increased amounts of a solution that contains either an allergen or placebo throughout the course of a day, while monitoring for symptoms of allergy. A few days later, the test is performed again with the solution that was not used the first time. Both the clinician and the patient are blinded to the contents of the solution. While this is the gold standard test. it carries with it inherent risks, such as anaphylaxis, and should only be performed in a facility where treatment can be received. In addition, it is a time and labor-intensive test, thus it is not commonly used.11 More commonly used is the open food challenge, which is single blinded and does not involve a placebo. The open food challenge is not only useful in ruling out allergy, but it is also useful in testing for tolerance to allergens, or whether the patient has outgrown an allergy.7

A general guideline for the evaluation of suspected food allergies is as follows. If the allergic reaction is mild to moderate (rash, urticaria), an lgE test or skin prick test should be performed. If negative, the food can be allowed back in the diet unless there is a strong history of anaphylactic reactions, in which case the food should be avoided until a supervised oral food challenge can be performed by an allergist. If the lgE or skin prick test is positive and the patient has a history of anaphylaxis, the food should be avoided and the patient set up with an anaphylaxis treatment plan that includes an epinephrine pen and a medical food allergy bracelet. If positive and no history of anaphylaxis, then further evaluation by an allergist with either a blinded or unblinded oral food challenge is appropriate.'•

PREVENTION

With the increase in prevalence of food allergies, an increased emphasis on prevention has been placed. Many different theories have been proposed to help prevent the development of food allergies and promote tolerance to common food allergens. The hygiene hypothesis is one of the most commonly known hypotheses behind both the development and prevention of food allergies. The hygiene hypothesis is that early exposure to a variety of microbes, pathogens and infections leads to a more diverse host microbiome, which leads to both increased immunity and development of oral tolerance of many common food allergens.'9•20 In contrast, the lack of early exposure to a variety of microbes, pathogens, and infections, or being overly "hygienic," leads to decreased immunity and increased allergies, including food allergies.12

Another common hypothesis is the dual-barrier hypothesis. This hypothesis states that allergen exposure happens both through oral and skin exposure as well as possibly through respiratory exposure. The hypothesis proposes that when children with atopy, mainly atopic dermatitis, are exposed to allergens through the skin, they experience an immune response that leads to the production of lgE antibodies against the particular allergen. This is the result of either a weakened or damaged skin barrier, which leads to increased allergic sensitization to foods.19•21 Thus, children with eczema tend to develop allergies more easily and more often than those without eczema. In contrast, children without eczema who are exposed to allergens through skin exposure early on have an increased likelihood of developing tolerance to the allergen and thus not developing an allergy.12-19-21

Some of the more popular preventive measures against food allergies that have garnered a decent amount of media attention, are the maternal diet during both pregnancy and lactation as well as the timing of dietary introduction of commonly allergenic foods.19 It has long been proposed that maternal consumption of foods such as peanuts, milk, tree nuts, and wheat during both pregnancy and lactation leads to fewer allergies.22 There have been very few studies on this, however, and the studies that have been conducted conclude that maternal consumption of highly allergenic foods such as peanuts, milk, tree nuts and wheat does not reduce the risk of food allergies.19

It was previously thought that allergic sensitization to foods happened by oral exposure to the food and thus it was thought that delaying exposure to potentially allergenic foods would help prevent food allergies. Thus, until 2007, guidelines recommended delaying the exposure to commonly allergenic foods up to three years of age.23•24 Since then, early introduction of commonly allergenic foods, however, has been studied and shown to be effective in preventing food allergies.22

The LEAP (Learning About Peanut Allergy) trial is a landmark randomized controlled trial that looked at whether or not the early oral introduction of peanuts into the diet led to a decrease in allergy to peanuts. The study population was children at high risk of developing peanut allergy between the ages of 4 and 11 months old in the UK. Children were randomly assigned to a group that would consume peanut products at least 3 times weekly and a group that would completely avoid peanuts until 60 months old. The study found that both early introduction and regular and ongoing consumption of peanut products led to a significant reduction (81%) in the number of children with peanut allergies at 60 months old. The results showed that 17.2% of children in the avoidance group, compared with 3.2% of children in the exposure group, had an allergy to peanuts at the end point of 60 months old.1•.22•2• This study demonstrated that early oral exposure is an effective way of preventing food allergies.

The current recommendation by the American Academy of Allergy, Asthma & Immunology is that the window of opportunity to prevent food allergies is from age 4 to 7 months. Thus, peanuts and peanut-containing foods along with other highly allergenic foods should be introduced to the child between 4 and 7 months of age. If the child has developed allergies or severe eczema in the first 4 to 6 months of life, the child should be evaluated by an allergist prior to introducing peanuts or other allergenic foods. In addition, it is also now known that delaying the introduction of potentially allergenic foods beyond 9 months of age may increase the child's risk of developing food allergies.23

Another more recent popular hypothesis for the development of food allergy suggests that Vitamin D deficiency may lead to increased food allergies.19Thus, normal Vitamin D levels would lead to a decrease in food allergies. A cohort study conducted in Australia demonstrated an association between Vitamin D deficiency and food allergy at 12 months old.19 Several other studies, however, have been conflicting. and suggest that while low levels of Vitamin D fromlowUVB exposure are a risk factor for allergy development, it is not a linear relationship and thus there may be several confounding factors.25

TREATMENT OF FOOD ALLERGIES

Food allergies may be an ever-increasing problem encountered in today's society, however, treatments for food allergies have not been well developed. There currently exists no definitive treatment for food allergies. The mainstays of treatment that should be recommended by a PCP include avoidance of food allergens and treatment of systemic or anaphylactic allergic reactions with epinephrine. Food labels are key to avoidance of food allergens and in the recent past have been mandated by the FDA to contain allergy-causing agents such as peanuts. Physicians can and should provide education to patients and their families about avoiding allergens, reading food labels, and signs and symptoms of anaphylaxis to look out for. In addition, a dietician maybe a helpful resource in learning how to avoid foods that may contain ingredients the child is allergic to.22•26

Physicians should also educate patients and their families about common food allergen cross-reactivity patterns. Cross-reactivity is common with class 2 food allergens and plant-derived proteins (Table 2). Cross-reactivity is typically either oral allergy syndrome with symptoms localized to the mouth, or latex-fruit syndrome with allergy to certain fruits and latex. Cross-reactive foods often are more allergenic when eaten raw as opposed to cooked.

TABLE2:

PLANT-DERIVED PROTEIN GROUP	ALLERGENS
Pathogen-related protein 2 group (glucanase) Pathogen-related protein 3 group (chitinase)	Latex,avocado,banana, chestnut, fig - Latex, avocado
Pathogen-related protein 5 (thaumatin-like)	Cherry,apple, kiwi
BirchBet v1 homologues hogen-related proteins10 BirchBet v2 homologues (celery-mugwort-spice} profilin		Apple,cherry,apricot,peach,
		pear,carrot, celery,parsley,
		hazelnut
	-		-
		Latex,celery, potato,pear,
		peanut,soybean

Examplesof class 2 foodallergens and their cross-reactivity."

I

Allergic reactions from cross-contaminations can also occur such as with peanuts and tree nuts, thus it is imperative that physicians know about cross-reactivity in order to properly educate and protect their patients."

Every patient with a food allergy should have two age appropriate non-expired epinephrine autoinjectors on hand at all times. Current guidelines for treatment of anaphylaxis include timely administration of epinephrine and adjunct therapy with corticosteroids and H1 blockers as well as airway protection. Timely administration of epinephrine prior to cardiac or respiratory comprise is the most important treatment for anaphylaxis and greatly improves survival rates.14•15

Research is currently in progress to investigate the effectiveness of immunologic therapies such as biologics, immunotherapy, and other pharmaceuticals.26 These studies are looking at the effects of subcutaneous, oral, epithelial, and sublingual immunotherapies and the reduction of allergies. The mechanism behind immunotherapy for the reduction of food allergies is to administer an allergen in incrementally increasing doses until a set maintenance dose has been reached. This can be done by introduction of the allergen through the routes listed above, with oralbeingthe most desiredroute. The allergenis then periodically given until the patient is no longer responsive to that allergen. The ultimate goal of immunotherapy is to achieve oral tolerance, or a "state of clinical unresponsiveness that persists regardless of allergen exposure."27

Currently, there are no FDA approved immunotherapies. Many studies have been performed on oral immunotherapies that show success in achieving tolerance or desensitization, especially to peanut protein, but it is still questionable whether or not desensitization persists once the immunotherapy is discontinued. The STOP II trial, a randomized controlled trial in 2104, showed tolerance to 1400mg of peanut protein in 62% of subjects. Many of these subjects experienced side effects, most notably nausea and vomiting but anaphylaxis and eosinophilic esophagitis were also noted.28•29

lmmunotherapy remains the most promising treatment option for many patients with food allergies. Thus far, efficacy to some extent has been shown for oral, sublingual, and epithelial immunotherapies. More research is still needed as well as a reduction in the number of adverse events occurring with immunotherapy treatment.28-29

CONCLUSION

Food allergies are a common and often life threatening condition that affects the lives of a growing number of children and families across the globe. While standardization of the diagnosis of food allergies remains a challenge, it is evident that there has been significant progress and promise both in the diagnosis and treatment of food allergies. What was once known as a condition that required total avoidance of a specific type of food and often all foods that were in the vicinity of the allergen at hand, is now a condition whose future treatment options show a lot of promise. Not only is research continually being conducted on new treatment options, but also with each new study there is more promise of a more permanent solution. The goal of food allergy treatment remains complete tolerance withasfew adverse events as possible.2829

New technologies are evolving that hopefully will lead to better treatment options and successful desensitization and tolerance of food allergens. A world where children can go to school and not have to worry about avoiding peanuts at all costs and carry epinephrine pens on them at all times is the ultimate goal, and one that the medical community is striving to achieve.

REFERENCES

1. Boyce,JA,Assa'ad,A, Burks,AW et al. Guidelines for the Diagnosisand Management of Food Allergy in the UnitedStates:Summary of the NIAID­ Sponsored Expert Panel Report. NutritionResearch. 2011;31:61-75.

2. Schneider Chafen, JJ,Newberry,SJ,Riedl, MA et al. Diagnosing and ManagingCommon FoodAllergies:A Systematic Review.JAMA 2010; 303(18):1848-1856,

3. Savage, J and Johns,CB.Food Allergy: Epidemiology and Natural History. lmmunolAllergyClinNorthAm.2015;35(1):45-59.

4. Nwaru,Bl, Hickstein, L, Panesar, SSet al. Prevalence of Common Food Allergiesin Europe: A Systematic Review and Meta-Analysis.Allergy. 2014; 69:992-1007,

5. Leleiko, NS,Cerezo,CS,and Shapiro, JM. New Concepts in FoodAllergy: ThePediatricGastroenterologist's View.Advances in Pediatrics. 2017; 64:87-109,

6. Sicherer,SH and Sampson, HA Food Allergy: Epidemiology, Pathogenesis, Diagnosis,and Treatment J AllergyClinlmmunol. 2014;133(2):291-307.

7. Kulis, M, Wright,BL,Jones,SM et al. Diagnosis, Management, and lnvestigational Therapies for FoodAllergies.Gastroenterology.2015; 148:1132-1142.

8. Carter,CA & Frischmeyer-Guerrerio, PA The Geneticsof Food Allergy. Curr Allergy Asthma Rep. 2018;18(1):2. doi:10.1007/s11882-018- 0756-z.

9. Valenta,R.Hochwallner, and H. Linhart. FoodAllergies: The Basics, Gastroenterology.2015;148:1120-1131.

10. Sathe,SK,Liu,C,and Zaffran,VD. Food Allergy.AnnuRevFoodSci Technol. 2016: 7:191-220.

11. Turnbull, JL,Adams,HN, and Gorard,DA ReviewArticle: TheDiagnosis and Management of Food Allergy andFood Intolerances. Aliment Pharmacol Ther.2015;41:3-25.

12. Leung,PSC,Shu,S,and Chang,C.The ChangingGeoepidemiologyof Food Allergies.ClinicRevAllerglmmunol. 2014;46:169-179.

13. Taylor.SL& Hefle,SL.Food Allergiesand Other FoodSensitivities.Food Technology. 2001;55(9):68-83.

14. Arnold,JJ and Williams,PM.Anaphylaxis:Recognition and Management. American Family Physician. 2011;84(10):1111-1118.

15. Turner. PJ,Jerschow,E.Umasunthar. T et al. FatalAnaphylaxis: Mortality Rate and Risk Factors.J Allergy Clin lmmunol Pract.2017;5(5):1169- 1178.

16. Chatterjee. RA Anaphylaxis in Children: Recognize and Treat Properly. ChildHealthExplanation. http://www.childhealth-explanation.com/ anaphylaxis-in-children.html.AccessedApril 9,2018.

17. Ho,MH.Wong,WH and Chang,C.Clinical Spectrum of FoodAllergies: a Comprehensive Review. 2014;46:225-240.

18. Kurowski,KandBoxer,RW.Food Allergies: Detection andManagement. American Family Physician. 2008;77(12):1678-1686.

19. ToilGD,Foong.RM, and Lack, G. Preventionof Food Allergy- Early Dietary Interventions. AllergologyInternational.2016;65:370-377.

20. Tilg.HandMoschen. AR Food. Immunity,and the Microbiome. Gastroenterology.2015;148:1107-1119.

21. Tordesillas, L, Berin,MC,andSampson,HA Immunology of Food Allergy. Immunity. 2017:47:38-50.

22. Wong, Y,Hussey Freeland. DM, and Nadeau,KC. FoodAllergy: Immune Mechanisms, Diagnosis and lmmunotherapy.Nat Revlmmunol. 2016; 16(12):751-765,

23. Larson, K, Mclaughlin,J,Stonehouse,Met al. IntroducingAllergenic Food IntoInfants'Diets:Systematic Review. MCN.2017;42(2):72-80.

24. Prescott,SL,Bouygue.GR, Videky,D et al. Avoidance or Exposureto Foods in PreventionandTreatment of Food Allergy? Curr OpinAllergy Clinlmmunol. 2010;10(3):258-266.

25. Rudders.SA and Camargo, CA Sunlight,VitaminD andFoodAllergy.Co­ Allergy.2015;15(4):350-357.

26. Yang, Y and Chiang, B. NovelApproaches to Food Allergy. Oinic RevAllerg Immunol.2014;46:250-257.

27. Hamad,A and Burks,W. OralToleranceand Allergy.Seminars in Immunology. 2017, http://dx.doi.org/10.1016/j.smim.2017.07.001.

28. Sampson,HA Food Allergy:Past, Present and Future.Allergology International.2016;65:363-369.

29. Koberenick, AK and Burks,AW. Active Treatment for FoodAllergy. Allergology International. 2016;65:388-395.