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Childhood Food Allergies: Current Diagnosis, Treatment, and Management Strategies

      Abstract

      Food allergy is a growing public health concern in the United States that affects an estimated 8% of children. Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a specific food. Nearly 40% of children with food allergy have a history of severe reactions that if not treated immediately with proper medication can lead to hospitalization or even death. The National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel in 2010 to develop guidelines outlining evidence-based practices in diagnosing and managing food allergy. The purpose of this review is to aid clinicians in translating the NIAID guidelines into primary care practice and includes the following content domains: (1) the definition and mechanism of childhood food allergy, (2) differences between food allergy and food intolerance, (3) the epidemiology of childhood food allergy in the United States, (4) best practices derived from the NIAID guidelines focused on primary care clinicians’ management of childhood food allergy, (5) emerging food allergy treatments, and (6) future directions in food allergy research and practice. Articles focused on childhood food allergy were considered for inclusion in this review. Studies were restricted to the English language and to those published within the past 40 years. A cross-listed combination of the following words, phrases, and MeSH terms was searched in PubMed and Google Scholar to identify relevant articles: food allergy, food hypersensitivity, child, pediatric, prevalence, and epidemiology. Additional sources were identified through the bibliographies of the retrieved articles.

      Abbreviations and Acronyms:

      EoE (eosinophilic esophagitis), FAHF (food allergy herbal formula), NIAID (National Institute of Allergy and Infectious Diseases), OIT (oral immunotherapy), QoL (quality of life), SCIT (subcutaneous immunotherapy), SLIT (sublingual immunotherapy)
      Article Highlights
      • The prevalence of childhood food allergy in the United States is approximately 8% and has increased during the past decade. The most common food allergens are milk, egg, wheat, soy, peanut, tree nut, finfish, and shellfish.
      • Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a specific food. Symptoms typically present within minutes to hours after ingestion. In contrast, food intolerance is not immune mediated and occurs because of pharmacologic, toxic, or metabolic properties of the food or the host.
      • Food allergy diagnosis requires documentation of a clinical history of a food allergic reaction. After ingestion of a specific food, a child may have mild symptoms (eg, a few hives, mild nausea/discomfort) and/or severe symptoms (eg, diffuse hives, shortness of breath, any respiratory symptom, obstructive swelling of tongue and/or lips that interferes with breathing, or circulatory symptoms).
      • Testing includes a food-specific IgE test and/or skin prick tests. A positive allergy test result in the absence of clinical symptoms is not adequate to make a diagnosis of food allergy.
      • All food-allergic patients should be prescribed antihistamines (mild reactions) and an epinephrine autoinjector device (severe reactions).
      • Comprehensive counseling regarding food allergy includes (1) food avoidance and appropriate nutritional monitoring, (2) label reading, (3) recognition of the signs and symptoms of anaphylaxis, (4) how and when to use the epinephrine autoinjector, (5) appropriate follow-up, and (6) documentation for school (eg, action plan).
      • Current research focuses on finding a treatment for food allergy. Several potential therapeutic modalities are being investigated and include oral immunotherapy, sublingual immunotherapy, and Chinese herbal medicine.
      Food allergy is a growing public health concern in the United States that affects an estimated 8% of children.
      • Branum A.M.
      • Lukacs S.L.
      Food allergy among children in the United States.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      Nearly 40% of children with food allergy have a history of severe reactions that if not treated immediately with proper medication can lead to hospitalization or even death.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      Because of the ubiquity of food throughout our lives, providing food-allergic children and their caregivers with the proper guidance to successfully manage their food allergy remains essential for protection against adverse health outcomes. Therefore, adequate clinician training on the proper diagnosis and comprehensive management of childhood food allergy is essential.
      Previous research suggests that primary care clinicians in the United States have many misconceptions regarding the diagnosis and management of food allergy.
      • Gupta R.S.
      • Springston E.E.
      • Kim J.S.
      • et al.
      Food allergy knowledge, attitudes, and beliefs of primary care physicians.
      Specifically, some clinicians were unaware of the most common food allergens and unable to instruct families in the appropriate administration of lifesaving medication (ie, epinephrine).
      • Gupta R.S.
      • Springston E.E.
      • Kim J.S.
      • et al.
      Food allergy knowledge, attitudes, and beliefs of primary care physicians.
      In addition, physicians expressed concern regarding their ability to manage food allergy effectively because of inadequate training in residency. Lack of quality studies and heterogeneity in accepted diagnostic practices have resulted in wide variations among clinicians’ food allergy management practices.
      • Chafen J.J.
      • Newberry S.J.
      • Riedl M.A.
      • et al.
      Diagnosing and managing common food allergies: a systematic review.
      In response to this variation, the National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel in 2010 to develop guidelines outlining evidence-based practices in diagnosing and managing food allergy.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      However, these guidelines have yet to be translated into clinical practice for specific subpopulations of physicians and affected patients.
      The purpose of this review is to provide primary care clinicians with relevant background on the current scientific literature, best practices, and emerging issues facing children with food allergies. To this end, the review includes the following content domains: (1) the definition and mechanism of childhood food allergy, (2) differences between food allergy and food intolerance, (3) the epidemiology of childhood food allergy in the United States, (4) best practices derived from the NIAID guidelines focused on primary care clinicians’ management of childhood food allergy, (5) emerging food allergy treatments, and (6) future directions in food allergy research and practice. Articles focused on childhood food allergy were considered for inclusion in this review. Studies were restricted to the English language and to those published within the past 40 years. A cross-listed combination of the following words, phrases, and MeSH terms was searched in PubMed and Google Scholar to identify relevant articles: food allergy, food hypersensitivity, child, pediatric, prevalence, and epidemiology. Additional sources were identified through the bibliographies of the retrieved articles.

      Definition and Mechanism of Food Allergy

      An adverse reaction to a food can encompass a broad array of events that occur after ingestion. Food allergy is a specific type of adverse event in which a pathologic immune-mediated (IgE) reaction to a specific allergen results after the item is exposed to the skin or a mucosal surface of the body, which is typically the gastrointestinal tract.
      • Vickery B.P.
      • Chin S.
      • Burks A.W.
      Pathophysiology of food allergy.
      Food allergies can be attributed to several factors including genetic predisposition and environmental exposure.
      • Lack G.
      • Fox D.
      • Northstone K.
      • Golding J.
      Avon Longitudinal Study of Parents and Children Study Team
      Factors associated with the development of peanut allergy in childhood.
      Most immunologic reactions to food allergies are IgE-mediated and target one or more specific proteins within a food called epitopes. Epitopes are the binding site for specific IgE or T cells. Most allergens are comprised of several different epitopes, and certain epitopes are homologous among food items and have been conserved through evolution (eg, peanut, tree nut, birch pollen).
      • Sastre J.
      Molecular diagnosis in allergy.
      Although the focus of this review is on IgE-mediated food allergy, it is important to recognize that a growing subset of food-allergic children suffer from non-IgE–mediated food allergy. A small percentage of food allergies is non-IgE mediated and involves T-cell–mediated immunity to certain food proteins. The major types of non-IgE–mediated food allergy are food protein–induced enterocolitis syndrome (FPIES), dietary protein intolerance (eg, milk protein allergy), protein enteropathy, and mixed IgE/non-IgE syndromes such as eosinophilic esophagitis (EoE). Celiac disease is an immune-mediated gastroenteropathy triggered by gluten, but this is not considered a food allergy.
      It is important to recognize these conditions as distinct from IgE-mediated food allergy for the following diagnostic and therapeutic reasons: (1) to understand that standard allergy skin prick testing and serologic IgE testing (ImmunoCAP or other similar systems) will not detect these conditions and that these are largely clinical diagnoses and (2) to understand that epinephrine and antihistamine will not treat these conditions.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Before discussing how the body responds to a food allergen, it is necessary to distinguish two processes that are easily confused: sensitization and allergy. Sensitization implies that the body makes allergen-specific IgE, which is detected in the blood or through skin testing. In contrast, allergy is defined by sensitization in conjunction with clinical symptoms in response to a trigger (eg, food allergen). Although food allergies are often associated with high levels of allergen-specific IgE levels, it is fundamental to understand that sensitization is not pathognomonic for food allergy. Sensitization can exist without a clinical response to the allergenic food. Therefore, isolated sensitization alone should not be used to diagnose food allergy.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In food-allergic individuals, it is widely believed that a normal mechanism of immune suppression occurs when exposure to an oral antigen fails within the gut. This process results in the loss of tolerance. It is believed that the structure of an allergenic protein resists breakdown or conformational change once it comes into contact with digestive enzymes, which allows it to retain its allergenicity. Failure of the digestive system to degrade proteins into smaller fragments results in the transluminal absorption of large, immunologically intact proteins. Once absorbed, antigen-presenting cells are able to bind these allergens and present them in association with major histocompatibility complex class II antigens for presentation to T cells within the lymph tissue. This is the first step of a complex cascade that results in the production of antigen-specific IgE antibodies or reactive T cells.
      In the case of IgE-mediated allergy, the antigen-specific IgE antibodies are produced and bind to the surface of mast cells. Bound IgE can then become cross-linked on recognition and binding of an allergen. These steps lead to degranulation, which is the process by which preformed chemicals (eg, histamine) are released from the mast cell and cause the symptoms we associate with an allergic reaction (Figure 1).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy.
      Figure thumbnail gr1
      Figure 1IgE response mechanism.
      From Middleton's Allergy: Principles and Practice,
      • Hus I.F.
      • Boyce J.A.
      Biology of mast cells and their mediators.
      with permission.

      Food Allergy vs Food Intolerance

      Food allergy is an immune-mediated response most commonly associated with IgE; food intolerance is a nonimmunologic response to a particular type of food. Food allergies are commonly due to egg, cow’s milk, wheat, soy, shellfish, fish, peanuts, and tree nuts whereas food intolerance may be attributable to food additives (eg, sulfates), lactose, and gluten.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report.
      Furthermore, food intolerance may be of a pharmacologic, toxic, or metabolic etiology, which includes lactase deficiency, impaired complex carbohydrate digestion, inhibition of diamine oxidase to metabolize histamine, and gluten sensitivity.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report.
      • Keeton Jr., R.W.
      • Baldwin J.L.
      • Singer A.M.
      Pharmacologic food reactions.
      For example, children with cow’s milk allergy may potentially experience hives and impaired breathing after allergen exposure. Conversely, children who are lactose intolerant lack the enzyme lactase. Clinically, this translates into the child being unable to metabolize milk, which can result in bloating, flatulence, and diarrhea. Moreover, gluten-associated disorders can be categorized into 3 types: (1) a person can have a nonimmunologic gluten intolerance, (2) a person can have a gluten food allergy that elicits an IgE response, and (3) a person can have celiac disease. Celiac disease differs from a food allergy because the reactions do involve the immune system but are relegated to the small intestine. Often, reactions can be confusing and require a clinician’s evaluation to determine if the reaction is a food allergy or food intolerance.

      Epidemiology of Childhood Food Allergy

      Prevalence

      Food allergy is a rapidly emerging public health issue that affects an estimated 8% of US children.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      In 2007, data from the National Health Interview Survey indicated that childhood food allergy prevalence had increased by 18% over the previous decade.
      • Branum A.M.
      • Lukacs S.L.
      Food allergy among children in the United States.
      According to the National Hospital Ambulatory Medical Care Survey, the increase in prevalence of pediatric food allergy parallels a rise in ambulatory care visits and food allergy–related hospitalizations.
      • Branum A.M.
      • Lukacs S.L.
      Food allergy among children in the United States.
      Furthermore, the rate of anaphylactic reactions requiring hospitalizations has substantially increased among young persons, with food-induced reactions being the most common cause.
      • Lin R.Y.
      • Anderson A.S.
      • Shah S.N.
      • Nurruzzaman F.
      Increasing anaphylaxis hospitalizations in the first 2 decades of life: New York State, 1990-2006.
      The 8 most common pediatric food allergens are peanut, tree nut, cow’s milk, shellfish, fin fish, egg, wheat, and soy.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Food allergy can be diagnosed in infants, children, and adolescents. Although allergies to certain foods can be triggered through food protein in the breast milk, food allergies are often detected and diagnosed as a child is being introduced to foods.

      Associations

      Although an explanation for the development of food allergy among certain children has not yet been clearly articulated, there are several known factors that are associated with food allergy, including specific demographic characteristics, existing atopic conditions, perinatal feeding habits, and infant diet.

      Demographic Characteristics

      Disparities may exist in food allergy prevalence and management. For example, previous research found that black and Asian children have significantly higher odds of food sensitization compared with white children; however, these children have significantly lower odds of receiving a formal physician diagnosis of food allergy.
      • Liu A.H.
      • Jaramillo R.
      • Sicherer S.H.
      • et al.
      National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.
      Similarly, a recent systematic review examining race and food allergy in the United States noted wide study heterogeneity and few quality studies evaluating these racial associations.
      • Greenhawt M.J.
      • Weiss C.C.
      • Conte M.
      • Doucet M.
      • Engler A.
      • Camargo Jr., C.
      Racial and ethnic disparity in food allergy in the United States: a systematic review.
      This review noted that no study utilized food challenge to diagnose food allergy, and the included studies had very different definitions of what was considered food allergy. However, 10 studies included in the review have documented either increased odds of food sensitization in black children or a significantly higher proportion of reported food allergy or sensitization in black children compared with white children. Income may also have a significant role because the odds of confirmed food allergy have been shown to be higher in households with incomes greater than $50,000.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.

      Existing Atopic Conditions

      Atopy is defined as the tendency to develop allergic diseases.
      • Sigurs N.
      • Hattevig G.
      • Kjellman B.
      • Kjellman N.I.
      • Nilsson L.
      • Björkstén B.
      Appearance of atopic disease in relation to serum IgE antibodies in children followed up from birth for 4 to 15 years.
      Typically, patients with one atopic condition are predisposed to development of multiple allergic conditions.
      • Leung D.Y.
      • Boguniewicz M.
      • Howell M.D.
      • Nomura I.
      • Hamid Q.A.
      New insights into atopic dermatitis.
      The allergic march is a theory that describes an often-observed triad of associated atopic conditions that progress from early into late childhood. The march starts in the first year of life with atopic dermatitis and progresses to allergic rhinitis, asthma, and food allergy.
      • Spergel J.M.
      From atopic dermatitis to asthma: the atopic march.
      This march has been observed in several birth cohorts outside the United States.
      • Schoetzau A.
      • Filipiak-Pittroff B.
      • Franke K.
      • et al.
      German Infant Nutritional Intervention Study Group
      Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age.
      The presence of severe eczema within the first 6 months of life has long been associated with an increased risk of developing peanut, milk, and egg allergy.
      • Lack G.
      • Fox D.
      • Northstone K.
      • Golding J.
      Avon Longitudinal Study of Parents and Children Study Team
      Factors associated with the development of peanut allergy in childhood.
      • Hill D.J.
      • Hosking C.S.
      • de Benedictis F.M.
      • Oranje A.P.
      • Diepgen T.L.
      • Bauchau V.
      EPAAC Study Group
      Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study.
      For children with asthma, there is an increased likelihood of food sensitization, and conversely, an increased likelihood of asthma has been noted in food-allergic individuals.
      • Lin R.Y.
      • Anderson A.S.
      • Shah S.N.
      • Nurruzzaman F.
      Increasing anaphylaxis hospitalizations in the first 2 decades of life: New York State, 1990-2006.
      • Schroeder A.
      • Kumar R.
      • Pongracic C.L.
      • et al.
      Food allergy is associated with an increased risk of asthma.
      • Gaffin J.M.
      • Sheehan W.J.
      • Morrill J.
      • et al.
      Tree nut allergy, egg allergy, and asthma in children.
      Asthma has long been recognized as a moderating factor in severe allergic reactions.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      Children with food allergy have a 4 times higher odds of having asthma.
      • Branum A.M.
      • Lukacs S.L.
      Food allergy among children in the United States.
      In addition, findings from a retrospective study indicate that 44% of children diagnosed as having asthma have an existing food allergy.
      • Simpson A.B.
      • Glutting J.
      • Yousef E.
      Food allergy and asthma morbidity in children.
      A recent study has also found that 30.4% of children with reported food allergy have multiple food allergies.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      This could be due to a tendency for an individual’s immune system to be hypersensitive, cross-reactive to structurally similar food allergens, or an artifact of having increased testing.

      Perinatal/Postnatal Maternal Eating Habits

      There is insufficient evidence to formally recommend that pregnant women avoid allergenic foods throughout pregnancy and while breastfeeding.
      • Lack G.
      Update on risk factors for food allergy.
      • Greer F.R.
      • Sicherer S.H.
      • Burks A.W.
      American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology
      Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas.
      Neither the American Academy of Pediatrics (AAP) nor the American Academy of Allergy, Asthma, and Immunology guidelines advocate for perinatal allergen avoidance. Although a 2006 Cochrane review found no evidence to support perinatal allergen avoidance,
      • Kramer M.S.
      • Kakuma R.
      Maternal dietary antigen avoidance during pregnancy or lactation, or both, for preventing or treating atopic disease in the child.
      there is a need for additional research and further consideration of the current recommendations.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Factors associated with avoidance, such as maternal quality of life (QoL), should also be considered in the overall risk-benefit analysis of perinatal dietary recommendations.

      Infant Diet

      There is insufficient evidence to determine recommendations regarding the avoidance of allergenic foods in the early years of infancy or to encourage delaying introduction of solid foods. Thus, parents often elect to avoid feeding their children commonly allergenic foods for fear of inducing allergy due to premature exposure in a developing immune system.
      • Hill D.J.
      • Hosking C.S.
      • de Benedictis F.M.
      • Oranje A.P.
      • Diepgen T.L.
      • Bauchau V.
      EPAAC Study Group
      Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study.
      Moreover, development of allergy in infants may be affected by both the timing and the quantity of exposure to allergenic foods.
      • Vickery B.P.
      • Scurlock A.M.
      • Jones S.M.
      • Burks A.W.
      Mechanisms of immune tolerance relevant to food allergy.
      The current AAP guidelines highlight one recommendation related to infant feeding: exclusively breastfeed the child for his or her first 4 to 6 months of life.
      • Greer F.R.
      • Sicherer S.H.
      • Burks A.W.
      American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology
      Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas.
      If there is strong suspicion for a milk or soy allergy, food protein–induced enterocolitis syndrome, or dietary protein intolerance, recommendations for formula change presented in Table 1 should be considered. Hopefully, further research in this area over the next several years will produce more clarity.
      Table 1Recommendations on Formula Choice by Food Allergy Condition
      Formula choiceCondition
      Milk allergySoy allergyFPIESDietary protein intoleranceColic or irritability
      Cow milk formulaBest alternative if not milk allergicSeek specialist evaluation if there is concern for milk allergy
      Soy formulaBest alternativeMay not be appropriate due to soy co-reactivityMay not be appropriate due to soy co-reactivityEmpiric switch for colic or irritability not recommended. Soy is an acceptable alternative for lactose intolerance
      Extensively hydrolyzed casein formulaGood alternativeGood alternativeMay not be appropriate for all milk-triggered FPIESsBest alternative, although a small percentage still react to thisEmpiric switch for colic or irritability not recommended
      Elemental formulaGood alternativeBest alternative if both milk and soy allergicBest alternativeGood alternativeEmpiric switch for colic or irritability not recommended
      FPIES = food protein–induced enterocolitis syndrome.

      Tolerance

      Tolerance develops at different rates according to food allergen. Factors that affect the development of tolerance include allergy to another food, tolerance to another food allergen, and other atopic conditions.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      For example, the average time to development of tolerance to soy was increased from 1 to 5 years in children who had coexisting asthma, allergic rhinitis, eczema, and other food allergies.
      • Savage J.H.
      • Matsui E.C.
      • Skripak J.M.
      • Wood R.A.
      The natural history of egg allergy.
      Another potentially predictive factor may be the level of initial serum IgE response to the food allergen.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      • Savage J.H.
      • Kaeding A.J.
      • Matsui E.C.
      • Wood R.A.
      The natural history of soy allergy.
      For wheat, tree nut, egg, cow’s milk, and soy allergy, lower initial and peak levels of antigen-specific IgE were associated with the development of tolerance.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      • Savage J.H.
      • Matsui E.C.
      • Skripak J.M.
      • Wood R.A.
      The natural history of egg allergy.
      • Savage J.H.
      • Kaeding A.J.
      • Matsui E.C.
      • Wood R.A.
      The natural history of soy allergy.
      • Skripak J.M.
      • Matsui E.C.
      • Mudd K.
      • Wood R.A.
      The natural history of IgE-mediated cow's milk allergy.
      • Keet C.A.
      • Matsui E.C.
      • Dhillon G.
      • Lenehan P.
      • Paterakis M.
      • Wood R.A.
      The natural history of wheat allergy.
      Lower peak IgE levels were also associated with more rapid development of tolerance for soy allergy.
      • Savage J.H.
      • Matsui E.C.
      • Skripak J.M.
      • Wood R.A.
      The natural history of egg allergy.
      • Savage J.H.
      • Kaeding A.J.
      • Matsui E.C.
      • Wood R.A.
      The natural history of soy allergy.
      Once tolerance has developed, recurrence of the allergy has been known to occur.
      • Sicherer S.H.
      • Sampson H.A.
      Peanut allergy: emerging concepts and approaches for an apparent epidemic.
      This phenomenon has been observed with peanut allergy and is more likely to occur with infrequent consumption of the allergenic food after it can be consumed safely.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Christie L.
      • Burks A.W.
      • Wood R.A.
      Peanut allergy: recurrence and its management.
      Research has indicated that once tolerance is established, eating the allergenic food frequently may decrease the likelihood of recurrence.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Christie L.
      • Burks A.W.
      • Wood R.A.
      Peanut allergy: recurrence and its management.
      In terms of long-term outcomes of having a food allergy, it remains unknown whether EoE is more likely to develop in formerly food-allergic individuals who develop tolerance; however, evidence of EoE development has been noted in oral immunotherapy (OIT) trials and may be related to long-term exposure in a formerly sensitive individual.
      • Skripak J.M.
      • Nash S.D.
      • Rowley H.
      • et al.
      A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.
      • Narisety S.D.
      • Skripak J.M.
      • Steele P.
      • et al.
      Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy.

      Severity

      Allergic reactions to foods can result in a combination of cutaneous, gastrointestinal, and respiratory manifestations that can potentially be fatal.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      • Gaffin J.M.
      • Sheehan W.J.
      • Morrill J.
      • et al.
      Tree nut allergy, egg allergy, and asthma in children.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      • Sampson H.A.
      • Muñoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      Predicting the severity of a subsequent reaction is difficult because it may vary and is independent of previous reaction history or serum IgE levels.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      • Vander Leek T.K.
      • Liu A.H.
      • Stefanski K.
      • Blacker B.
      • Bock S.A.
      The natural history of peanut allergy in young children and its association with serum peanut-specific IgE.
      However, research on the natural history of peanut allergy suggests an association may exist between reaction severity and IgE level.
      • Neuman-Sunshine D.L.
      • Eckman J.A.
      • Keet C.A.
      • et al.
      The natural history of persistent peanut allergy.
      In a recent study, 40% of children with a food allergy had already experienced a severe reaction.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      Severe reactions are more likely to occur in adolescents aged 14-17 years and in youths who have multiple food allergies.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      • Shah E.
      • Pongracic J.
      Food-induced anaphylaxis: who, what, why, and where?.
      Peanut, tree nut, and shellfish allergies are the most likely to result in severe reactions.
      • Gupta R.S.
      • Springston E.E.
      • Warrier M.R.
      • et al.
      The prevalence, severity, and distribution of childhood food allergy in the United States.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      • Sampson H.A.
      • Muñoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      Among tree nuts, cashews and walnuts account for the majority of severe reactions.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      Severity is a purely clinical observation and cannot yet be predicted by the magnitude of results of skin or blood tests (eg, higher scores do not necessarily indicate a more severe allergy).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In addition, severity of a reaction is also highly influenced by recognition and prompt treatment. Even a seemingly mild reaction has the potential to quickly progress to a severe reaction if not addressed quickly and monitored.

      NIAID Guidelines for the Diagnosis and Management of Food Allergy

      Primary care clinicians are often the first resource for affected families and play a critical role in the diagnosis and management of childhood food allergy. Accordingly, recognition and proper management of food allergy in the primary care setting is critical and may be lifesaving. To better equip primary care physicians in managing patients with food allergy, we have distilled the NIAID guidelines into the following 5 categories to ensure optimal management in the primary care setting: (1) clinical history of reactions, (2) diagnostic testing and test interpretation, (3) prescription of potentially lifesaving medications, (4) counseling and education for patients and caregivers, and (5) referral to an allergist (Figure 2).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Common food allergy scenarios in the primary care setting are shown in Table 2. A resource list of reputable food allergy organizations has also been provided to help guide primary care physicians in the management of childhood food allergy (Supplemental Appendix, available online at http://www.mayoclinicproceedings.org).
      Figure thumbnail gr2
      Figure 2Food allergy management protocol.
      Data from Nutr Res.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.
      Table 2Eight Common Food Allergy Scenarios in the Primary Care Setting: Appropriate Action and Rationale
      ScenarioAppropriate actionRationale
      A parent of a baby <1 y presents with one of the following complaints:
      • Colic/irritability
      • Constipation
      • Watery stool
      • Reassurance, evaluation, or treatment of the underlying issue (eg, stool softener, normal variation)
      • No need to change formula at this time
      • The diagnosis of food allergy is unlikely, and the symptoms provide no evidence of an immunologic disorder
      • Further evaluation is needed to explore these complaints
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      A mother of a newborn seeks advice about which foods she should avoid while breast-feeding to prevent development of allergy. Alternatively, a pregnant mother inquires about what not to eat during pregnancy to prevent food allergy in her child
      • There is currently no evidence supporting avoidance of any particular food during pregnancy or during breast-feeding
      • Conflicting data exist
      • No clear recommendation can be made
      • No longitudinal prospective study has been published to address these concerns, although 2 English studies are under way
      • There is emerging evidence that early child exposure may be beneficial in preventing specific food allergies
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
        • Fleischer D.M.
        • Spergel J.M.
        • Assa'ad A.H.
        • Pongracic J.A.
        Primary prevention of allergic disease through nutritional interventions.
        • Du Toit G.
        • Katz Y.
        • Sasieni P.
        • et al.
        Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
      A child presents with atopic dermatitis, and the parent expresses concern about food allergy based on what they have heard or read
      • Obtain a detailed history to determine the likelihood that food exposure is provoking a discrete episode of atopic dermatitis and the degree of underlying atopic dermatitis
      • Treat the eczema using moisturizers and appropriate-potency topical corticosteroids. Ask parent to keep a diary of food eaten before an breakout for a month to help clarify cause and effect
      • Food allergy is a potential cause in only 35% of those with moderate to severe atopic dermatitis
      • The older allergy literature overspecifies a relationship between food-specific IgE and food allergy in this population, and care must be taken to not overtest or interpret the results too literally
      • Often, avoidance is prescribed and no treatment for the underlying atopic dermatitis is provided
      • Allergy referral is recommended
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
        • Greenhawt M.
        The role of food allergy in atopic dermatitis.
      A parent raises concern about the increasing prevalence of food allergy and desires either blood testing or allergy referral for their child
      • Reassure the parent that allergy testing is not accurate enough to predict what someone may be allergic to and can only help in the evaluation of a suspected allergic reaction that has occurred
      • Allergy testing cannot “predict” future risk. Also, IgE testing has a poor positive predictive value. The tests are sensitive and generally detect any allergen-specific IgE to food that is present, but it is often poorly understood that simply having allergen-specific IgE is not indicative of having an allergy (eg, having the antibody does not necessarily indicate disease)
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
        • Fleischer D.M.
        • Spergel J.M.
        • Assa'ad A.H.
        • Pongracic J.A.
        Primary prevention of allergic disease through nutritional interventions.
      A child presents with what is deemed a “mild” food allergy, with a history of hives associated only with a particular food
      • Anaphylaxis management must be provided, an epinephrine autoinjector should be prescribed, and the child should be trained to use it
      • Referral to an allergy specialist for longitudinal care is recommended
      • Any food allergy can be progressively more severe on the next exposure. All children with food allergy should be given epinephrine and be trained to use it. Yearly follow-up is recommended for retesting
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      A parent seeks food testing for their child based on a “family history” of a food allergy in a close relative
      • Obtain a thorough history and establish if your patient has had difficulty with any food or if food is being withheld because of the concern. If so, consultation with an allergist is recommended
      • There is minimal evidence that family history poses much risk. The younger sibling of a peanut-allergic child does have a mildly elevated risk of peanut allergy and should be referred to an allergist for further evaluation
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
        • Sicherer S.H.
        • Sampson H.A.
        Peanut allergy: emerging concepts and approaches for an apparent epidemic.
        • Hourihane J.O.
        • Dean T.P.
        • Warner J.O.
        Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges.
      An egg-allergic child presents for an influenza or MMR vaccination (both contain trace amounts of egg)
      • Provide the vaccination in your office and observe as you would any other child per ACIP guidelines
      • The risk of MMR provoking a reaction in an egg-allergic child was disproven in 1995. Similarly, the risk for influenza vaccine was disproven in 2011, and the ACIP changed their formal guidelines
        • Kelso J.M.
        • Greenhawt M.J.
        • Li J.T.
        • et al.
        Adverse reactions to vaccines practice parameter 2012 update.
        • Greenhawt M.J.
        • Spergel J.M.
        • Rank M.A.
        • et al.
        Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy.
      A child presents to your office after being treated with epinephrine in the emergency department for acute development of cough, hives, and vomiting within 2-3 h after exposure to a tree nut (or any food)
      • Obtain a complete history, keeping in mind the high probability that this was indeed provoked by the food
      • Prescribe an epinephrine autoinjector and provide training on how to use it
      • Refer to an allergist and instruct that the child avoid that particular food item until further evaluation can be conducted
      • This presentation would be suggestive of a food allergy in a patient of any age. In children with such a specific history, testing would likely be confirmatory and can be done at any age. This child should be immediately referred to an allergy specialist, told to temporarily avoid that particular food, and be prescribed an epinephrine autoinjector
        • Boyce J.A.
        • Assa'ad A.
        • Burks A.W.
        • et al.
        NIAID-Sponsored Expert Panel
        Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      ACIP = Advisory Committee on Immunization Practices; MMR = measles-mumps-rubella.

      Clinical History of Reactions

      Primary care clinicians are often the first to assess a child with suspected new-onset food allergy. Examples of mild to moderate food allergy symptomatology include angioedema of the lips, eyes, face, or other body parts, oropharyngeal symptoms, eczema, flushing, hives, pruritus, and vomiting.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Examples of severe food allergy symptomatology include low blood pressure or syncope, dyspnea, wheezing or any respiratory difficulty, or multiple organ system involvement. Anaphylaxis criteria have been established and reviewed elsewhere, but briefly, they involve cardiac/circulatory symptoms, respiratory symptoms, or any presentation involving 2 organ systems (eg, severe gastrointestinal and skin symptoms).
      • Sampson H.A.
      • Muñoz-Furlong A.
      • Bock S.A.
      • et al.
      Symposium on the definition and management of anaphylaxis: summary report.
      The differential diagnosis for food allergy includes metabolic intolerance, toxic effects of foods, food poisoning, metabolic deficiencies, and food aversions.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In cases in which a food allergy is suspected, the food should be eliminated from the diet. Removal of the offending agent should prevent further symptoms from developing. Care must be taken to factor in the confounding influence of observer bias when undertaking an at-home elimination diet, especially if atopic dermatitis is the presenting symptom. Patients who undergo dietary elimination for suspected food allergy should be referred to an allergist.

      Diagnostic Testing and Test Interpretation

      Allergy tests are used to confirm suspected cases of food allergy. Testing without suspicion of a symptom-provoking episode is not recommended, and findings are often misleading or inaccurate because of false-positive results.
      • Portnoy J.M.
      Appropriate allergy testing and interpretation.
      Three diagnostic tests include the skin prick test, the specific serum IgE test, and the oral food challenge. Atopy patch testing, intradermal food testing, and IgG4 food testing are not recommended for assessment of food allergy.
      Skin prick tests are currently conducted by specialists in allergy or immunology. Skin testing directly assesses the presence of mast cell–bound allergen-specific IgE. Skin prick testing involves introduction of allergen extracts into the skin. A positive reaction is defined as a wheal at least 3 mm greater than the negative control. The negative predictive value is more than 95%, while the positive predictive value is less than 50%; therefore, there are many false-positive results. Antihistamines should be discontinued before testing.
      Serum IgE tests quantify free specific serum IgE but do not measure IgE bound to mast cells that participate in a reaction. IgE tests are available to primary care physicians and may be of benefit during the initial assessment, as long as testing is limited to what reasonably may have provoked the reaction.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Use of laboratory-offered standard panels of common foods should be discouraged. All positive and negative test results need to be correlated with the patient’s clinical history. A positive test result alone does not establish the diagnosis of clinical food allergy. Rather, it provides evidence of sensitization, ie, an immunologic response.
      • Bernstein I.L.
      • Li J.T.
      • Bernstein D.I.
      • et al.
      American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology
      Allergy diagnostic testing: an updated practice parameter.
      Oftentimes, however, primary care physicians have varying comfort levels in interpreting laboratory tests to diagnose food allergy, and many do not feel adequately prepared by their medical training to care for children with food allergy.
      • Gupta R.S.
      • Springston E.E.
      • Kim J.S.
      • et al.
      Food allergy knowledge, attitudes, and beliefs of primary care physicians.
      The cutoff value is the concentration of specific IgE for a particular food allergen that is 90% predictive of a clinical reaction to the food. Increasing levels of specific IgE and wheal response to skin prick testing beyond the cutoff level correlate with an increased likelihood of having clinical food allergy but not necessarily with reaction severity. For example, established cutoff values for serum-specific IgE testing include: egg (child 3-17 years), 7 kU/L; egg (child ≤2 years), 2 kU/L; cow’s milk (child 3-17 years), 15 kU/L; cow’s milk (child ≤2 years), 5 kU/L; peanut (child <18 years), 14 kU/L; and fish (child <18 years), 20 kU/L.
      Oral food challenge is a procedure that should only be undertaken by an allergist. The procedure involves incremental feeding of a prespecified amount of a food (either in an open or blinded procedure) under strict medical supervision. Emergency medication must be on hand in case of an allergic reaction. Oral food challenge has been described in detail elsewhere.
      • Nowak-Węgrzyn A.
      • Assa'ad A.H.
      • Bahna S.L.
      • Bock S.A.
      • Sicherer S.H.
      • Teuber S.S.
      Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology
      Work Group report: oral food challenge testing.

      Prescription of Potentially Lifesaving Medications

      Food avoidance is the first line of treatment for children with food allergies because there are no recommended preventive medications.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In addition to food avoidance, primary care clinicians should prescribe both antihistamines and an epinephrine autoinjector for all children presenting with a likely food allergy. Parents and caretakers should be directed to use antihistamines for mild symptoms (eg, a few hives, mild nausea/discomfort) and the epinephrine autoinjector for severe symptoms (eg, diffuse hives, shortness of breath, any respiratory symptom, obstructive swelling of the tongue and/or lips that interferes with breathing, or circulatory symptoms). Antihistamines should not be used in place of epinephrine.
      For severe reactions, epinephrine will relieve symptoms and can be dosed every 5 to 15 minutes if symptoms are not responding.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Fatalities due to anaphylactic reactions to foods.
      • Bock S.A.
      • Muñoz-Furlong A.
      • Sampson H.A.
      Further fatalities caused by anaphylactic reactions to food, 2001-2006.
      • Sampson H.A.
      • Muñoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      In some cases, a child may require a second dose of epinephrine; thus, patients are advised to carry 2 epinephrine autoinjectors in case of an emergency. Adjunctive treatment for severe reactions includes bronchodilators, H1 and H2 antihistamines, corticosteroids, vasopressors, glucagon, and atropine.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In any reaction, corticosteroids have limited benefit because their role is to prevent late-onset activation of immune mediators (such as leukotrienes) that are recruited to the site of reaction, in what is called a biphasic reaction. The importance of coadministering both H1 and H2 antihistamines is an emerging focus of anaphylaxis education to prevent severe cardiac deficit.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization anaphylaxis guidelines: summary.
      Previous research has shown that patients wait an average of 4 months after a referral for their first allergist consultation.
      • Gupta R.
      • Lau C.H.
      • Springston E.E.
      • Smith B.
      • et al.
      Childhood Food Allergy Tolerance and Associated Factors. (Abstract).
      In the interim, the child has the potential to experience an additional adverse food allergy–related event. Hence, even if primary care clinicians are uncertain of the food allergy diagnosis, they should always prescribe potentially lifesaving epinephrine and antihistamines and counsel caretakers and children on appropriate food allergy management.

      Counseling and Education for Patients and Caregivers

      Providing comprehensive counseling to families of children with food allergy remains integral to keeping the child with food allergies safe. Comprehensive counseling includes (1) food avoidance and appropriate nutritional monitoring, (2) label reading, (3) recognition of the signs and symptoms of anaphylaxis, (4) how and when to use the epinephrine autoinjector, (5) appropriate long-term follow-up to assess longitudinal prognosis, development of potential tolerance, and development of other allergic conditions, and (6) provision of documentation for school (eg, food allergy emergency action plan, individualized education plan [IEP]/Section 504 plans).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      Primary care clinicians should always train affected families in recognition of symptoms and appropriate epinephrine administration. They also can and should create an emergency action plan for the child and train his or her family in appropriate emergency food allergy action plan implementation (Figure 3). Please refer to the following website, www.foodallergy.org, for an updated version of the food allergy action plan. Depending on the specific food or number of foods removed from the diet, nutritional counseling is often not only helpful to preserve the family’s QoL but may also be medically necessary to prevent malnutrition.
      • Tiainen J.M.
      • Nuutinen O.M.
      • Kalavainen M.P.
      Diet and nutritional status in children with cow's milk allergy.
      • Primeau M.N.
      • Kagan R.
      • Joseph L.
      • et al.
      The psychological burden of peanut allergy as perceived by adults with peanut allergy and the parents of peanut-allergic children.
      • Christie L.
      • Hine R.J.
      • Parker J.G.
      • Burks W.
      Food allergies in children affect nutrient intake and growth.
      Figure thumbnail gr3a
      Figure 3Food allergy emergency action plan form.
      From http://www.foodallergy.org/treating-an-allergic-reaction,

      Food Allergy Researcha and Education. Treatment and managing reactions. http://www.foodallergy.org/treating-an-allergic-reaction.

      with permission.
      Figure thumbnail gr3b
      Figure 3Food allergy emergency action plan form.
      From http://www.foodallergy.org/treating-an-allergic-reaction,

      Food Allergy Researcha and Education. Treatment and managing reactions. http://www.foodallergy.org/treating-an-allergic-reaction.

      with permission.
      The child’s food allergy will need to be managed at home, at school, and within his or her community. It remains integral to the safety of the child that all institutions (eg, school) and people who come into contact with the child (eg, coaches, schoolmates) are aware of the child’s food allergy. To assist in managing the child’s diet, children with food allergy, their families, and other persons entrusted with care of the child should receive education on reading labels, sources of exposure to the allergen, and use of self-injectable epinephrine. This is of particular importance for child care providers but also others such as grandparents who may supervise an allergic child. In addition, families are often advised to provide their child with medical identification jewelry in the case of an emergency outside of the child’s home.

      Referral to an Allergist

      Children presenting with a clinical history of likely food allergy should be referred to an allergist for diagnostic testing.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      In some circumstances, it is necessary to perform an oral food challenge to verify the history. Although the current criterion standard for diagnosing true food allergy is a double-blind, placebo-controlled oral food challenge, there is an emerging trend toward use of open challenges.
      • Pongracic J.A.
      • Bock S.A.
      • Sicherer S.H.
      Oral food challenge practices among allergists in the United States.
      In addition, the allergist will formulate an emergency anaphylaxis action plan, reinforce how and when to use epinephrine, provide anticipatory guidance pertaining to avoidance strategies (eg, label reading), and help to facilitate a dialogue with schools or child care centers, if necessary. Primary care physicians should be encouraged to comanage the condition with the allergist and should be aware of the special needs of the food-allergic individual. This may include social support given the effects that food allergy can have on QoL.
      • Springston E.E.
      • Smith B.
      • Shulruff J.
      • Pongracic J.
      • Holl J.
      • Gupta R.S.
      Variations in quality of life among caregivers of food allergic children.

      Emerging Food Allergy Treatments

      Avoidance Diets

      Avoidance diets are a mainstay of the management of food allergy, although there are no controlled studies evaluating their efficacy.
      • Chafen J.J.
      • Newberry S.J.
      • Riedl M.A.
      • et al.
      Diagnosing and managing common food allergies: a systematic review.
      Initiating an elimination diet is an important step that bears an important responsibility. Avoiding an “obvious” trigger is straightforward, although care must be taken to not solely rely on sensitization as the only determination of allergy if the history does not strongly support allergy. Handling of potentially cross-reactive foods is more difficult (eg, peanut, tree nut).
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel.
      • Bernstein I.L.
      • Li J.T.
      • Bernstein D.I.
      • et al.
      American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology
      Allergy diagnostic testing: an updated practice parameter.
      There is limited data on the known actual risk with most cross-reactivity, as opposed to the theoretical risk described by experts, although the clinical experience with cross-reactivity has been conservative, favoring avoidance. Overreliance on serum-specific IgE testing indicating “allergy” contributes to this practice. In a recent study, Fleischer et al
      • Fleischer D.M.
      • Bock S.A.
      • Spears G.C.
      • et al.
      Oral food challenges in children with a diagnosis of food allergy.
      very eloquently demonstrated how unnecessary many of the widespread dietary elimination diets are. They showed that nearly 89% of avoidance diets in 125 children with atopic dermatitis and food allergy (diagnosed by serum specific IgE) were unnecessary. Nutritional deficits have been reported from widespread dietary avoidance.
      • Liu T.
      • Howard R.M.
      • Mancini A.J.
      • et al.
      Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance.
      Nutritional consultation is highly recommended for children in whom widespread avoidance is necessary. It is known that as the number of food avoidances increases, QoL diminishes, which promotes poor adaptation and anxiety in the family.
      • Primeau M.N.
      • Kagan R.
      • Joseph L.
      • et al.
      The psychological burden of peanut allergy as perceived by adults with peanut allergy and the parents of peanut-allergic children.
      • Patel N.
      • Boyle R.J.
      • Warner J.O.
      • et al.
      Anxiety in children with food allergy.
      Strategies to prevent unnecessary avoidance include use of challenge to confirm food allergy (when indicated), avoiding changing from cow’s milk formula to other formulas for colicky children without true signs of IgE/non-IgE–mediated allergy, and discontinuation of the practice of screening children without a history of an exposure with a reaction.
      The standard approach for management of food allergies has been complete avoidance of the allergen and clinical management of symptoms on accidental exposure. However, although successful avoidance can prevent the occurrence of allergic reactions, it is difficult to ensure avoidance at all times because of the ubiquitous presence of food in our society. Not only is allergen avoidance difficult to execute, it is also associated with increased anxiety and impaired QoL.
      • Primeau M.N.
      • Kagan R.
      • Joseph L.
      • et al.
      The psychological burden of peanut allergy as perceived by adults with peanut allergy and the parents of peanut-allergic children.
      • Springston E.E.
      • Smith B.
      • Shulruff J.
      • Pongracic J.
      • Holl J.
      • Gupta R.S.
      Variations in quality of life among caregivers of food allergic children.
      Thus, recently there has been a particular focus on the search for treatment or a cure. Several potential therapeutic modalities are being investigated. These include OIT and sublingual immunotherapy (SLIT) in addition to Chinese herbal medicine.

      Immunotherapy

      Oral immunotherapy takes advantage of the body’s natural tendency to tolerate items presented to the immune system through oral exposure. Through repeated oral exposure to incremental amounts of a particular food allergen, immunotherapy is theorized to induce a change in the immune system by promoting regulatory T cells. This process is modulated by the transcription factor FoxP3 and mediated by the cytokines interleukin 10 and transforming growth factor β. This change is accompanied by up-regulation of allergen-specific IgG4 and decrease of IgE. The overall intended effect of the process is tolerance; however, OIT may also result in desensitization.
      • Scurlock A.M.
      • Vickery B.P.
      • Hourihane J.O.
      • Burks A.W.
      Pediatric food allergy and mucosal tolerance.
      Adverse effects of OIT vary widely, ranging from mild oropharyngeal or skin reactions to anaphylaxis.
      The basis of any immunotherapy is similar to that for standard subcutaneous immunotherapy (SCIT), colloquially known as “allergy shots.” In SCIT, individuals are gradually immunized via injection to their identified allergens, starting with a very dilute concentration and increasing it until a maintenance peak dose is reached that will alter the body’s response to the allergen. The body is exposed to incremental increases in the potency and quantity of the allergen until a tolerance is reached, reflected by the aforementioned cytokine changes. SLIT is an alternative form of OIT that is also being investigated as a food allergy therapy.
      • Scurlock A.M.
      • Vickery B.P.
      • Hourihane J.O.
      • Burks A.W.
      Pediatric food allergy and mucosal tolerance.
      • Incorvaia C.
      • Mauro M.
      • Cappelletti T.
      • Pravettoni C.
      • Leo G.
      • Riario-Sforza G.G.
      New applications for sublingual immunotherapy in allergy.
      SLIT is also administered orally as both drops or tablets, which are either swallowed or held under the tongue and spit out. The allergen is taken up by mucosal antigen-presenting cells (eg, Langerhans cells, myeloid dendritic cells) in a mechanism distinct from SCIT and OIT.
      • Calderón M.A.
      • Simons F.E.
      • Malling H.J.
      • Lockey R.F.
      • Moingeon P.
      • Demoly P.
      Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile.
      The use of SLIT is associated with a very low incidence of anaphylactic or life-threatening reactions. Adverse effects are generally limited to mild oropharyngeal, pruritic cutaneous, or gastrointestinal symptoms.
      • Pham-Thi N.
      • de Blic J.
      • Scheinmann P.
      Sublingual immunotherapy in the treatment of children.
      • Pajno G.B.
      Sublingual immunotherapy: the optimism and the issues.
      Both OIT and SLIT are being studied for the treatment of egg, milk, and peanut allergy in the United States, including National Institutes of Health–sponsored studies at 5 university centers. Preliminary open and placebo-controlled studies in the United States have demonstrated that most patients can be successfully desensitized with limited adverse events. Desensitization requires continuous reexposure to the allergen and is distinct from tolerance, which implies the ability to have interrupted exposure.
      • Skripak J.M.
      • Nash S.D.
      • Rowley H.
      • et al.
      A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.
      • Narisety S.D.
      • Skripak J.M.
      • Steele P.
      • et al.
      Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy.
      • Kim E.H.
      • Bird J.A.
      • Kulis M.
      • et al.
      Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.
      • Keet C.A.
      • Frischmeyer-Guerrerio P.A.
      • Thyagarajan A.
      • et al.
      The safety and efficacy of sublingual and oral immunotherapy for milk allergy.
      • Jones S.M.
      • Pons L.
      • Roberts J.L.
      • et al.
      Clinical efficacy and immune regulation with peanut oral immunotherapy.
      • Varshney P.
      • Jones S.M.
      • Scurlock A.M.
      • et al.
      A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.
      • Buchanan A.D.
      • Green T.D.
      • Jones S.M.
      • et al.
      Egg oral immunotherapy in nonanaphylactic children with egg allergy.
      • Mousallem T.
      • Burks A.W.
      Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy.
      More specifically, a recent study by Burks et al
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Consortium of Food Allergy Research (CoFAR)
      Oral immunotherapy for treatment of egg allergy in children.
      showed that after 24 months of egg OIT, only 28% of patients achieved sustained unresponsiveness to egg after discontinuing their treatment for 8 weeks.
      The exact mechanism of action of immunotherapy remains unclear. Patients in OIT trials have suffered anaphylaxis, both during in-office and home dosing phases, and participants have withdrawn from studies because of severe reactions or the inability to progress through the protocol. The most common adverse effects with SLIT have been mild and include oral pruritus, cutaneous pruritus, and diarrhea/abdominal pain.
      • Tucker M.H.
      • Tankersley M.S.
      ACAAI Immunotherapy and Diagnostics Committee
      Perception and practice of sublingual immunotherapy among practicing allergists.
      Long-term outcomes for both therapies, including development of tolerance or adverse effects such as EoE, are unknown. A non-US OIT trial investigating peanut allergies demonstrated limited proof that tolerance could last for 2 weeks after interruption of daily dosing.
      • Blumchen K.
      • Ulbricht H.
      • Staden U.
      • et al.
      Oral peanut immunotherapy in children with peanut anaphylaxis.
      A recent US OIT trial investigating egg allergies showed tolerance in a subset of participants that lasted up to 4 to 6 weeks after treatment interruption.
      • Burks A.W.
      • Jones S.M.
      • Wood R.A.
      • et al.
      Consortium of Food Allergy Research (CoFAR)
      Oral immunotherapy for treatment of egg allergy in children.
      Neither OIT nor SLIT is Food and Drug Administration approved for use in the United States. These therapies are currently in highly experimental phase 1/2a trials, and their efficacy in young patients or patients with severe reactivity has not been investigated. However, there is some evidence of off-label, non–research-based prescribing of these therapies among allergists and otolaryngologists in practice.
      • Traister R.S.
      • Green T.D.
      • Mitchell L.
      • Greenhawt M.
      Community opinions regarding oral immunotherapy for food allergies.

      Chinese Herbal Medicine

      Chinese herbal medicine is another potential therapy for food allergies. Several Chinese herbs are reported to have anti-inflammatory and antiallergenic properties. Two specific formulations, labeled food allergy herbal formula (FAHF) 1 and 2, are 11- and 9-herb formulations, created by researchers at Mount Sinai School of Medicine.
      • Wang J.
      • Sicherer S.H.
      Immunologic therapeutic approaches in the management of food allergy.
      Murine and early-phase human trials have demonstrated that these formulations can suppress the T helper cell type 2 (allergenic) response through diminished basophil activation and interleukin 5 levels.
      • Patil S.P.
      • Wang J.
      • Song Y.
      • et al.
      Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from patients with food allergy: extended phase I study.
      In the mouse model in particular, FAHF-2 blocked both the progression of existing food allergy and the development of new food allergy to peanut, fish, and egg.
      • Wang J.
      • Sicherer S.H.
      Immunologic therapeutic approaches in the management of food allergy.
      Most importantly, FAHF-2 demonstrated no harmful effects for patients and is currently undergoing phase 3 study.
      • Patil S.P.
      • Wang J.
      • Song Y.
      • et al.
      Clinical safety of Food Allergy Herbal Formula-2 (FAHF-2) and inhibitory effect on basophils from patients with food allergy: extended phase I study.
      • Wang J.
      • Patil S.P.
      • Yang N.
      • et al.
      Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study.

      Conclusion

      Food allergy is a serious and growing health concern in the United States. Primary care clinicians are often the first resource for affected families and play a critical role in the diagnosis of food allergy in children. Recognition and proper management of food allergy in the primary care setting is critical and may prove lifesaving. Accordingly, familiarity with NIAID guidelines for the diagnosis and management of food allergy is essential. The primary care physician can and must play an integral role in supporting the family and advise families on avoidance strategies, safe eating habits, emergency medications, and emergency action plans. At present, strict avoidance is the best management strategy, although therapies such as OIT, SLIT, and Chinese herbal medicine provide hope that one day a viable treatment or cure will become a reality.

      Supplemental Online Material

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