J
Allergy Clin Immunol. Author manuscript; available in PMC 2014 Nov 24. Published in final edited form as: PMCID: PMC4241964 NIHMSID: NIHMS247178 Report of the NIAID-Sponsored Expert Panel Joshua A. Boyce, MD,
Amal Assa'ad, MD, A. Wesley Burks, MD, Stacie M. Jones, MD,
Hugh A. Sampson, MD, Robert A. Wood, MD, Marshall Plaut, MD,
Susan F. Cooper, MSc, Matthew J. Fenton, PhD, S. Hasan Arshad,
MBBS, MRCP, DM, FRCP, Sami L. Bahna, MD, DrPH, Lisa A. Beck, MD,
Carol Byrd-Bredbenner, PhD, RD, FADA, Carlos A. Camargo, Jr, MD, DrPH,
Lawrence Eichenfield, MD, Glenn T. Furuta, MD, Jon M.
Hanifin, MD, Carol Jones, RN, AE-C, Monica Kraft, MD, Bruce D.
Levy, MD, Phil Lieberman, MD, Stefano Luccioli, MD, Kathleen
M. McCall, BSN, RN, Lynda C. Schneider, MD, Ronald A. Simon, MD,
F. Estelle R. Simons, MD, Stephen J. Teach, MD, MPH, Barbara P.
Yawn, MD, MPH, MSc, and Julie M. Schwaninger, MSc Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no
current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute
of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated
with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research. Keywords: food, allergy, anaphylaxis, diagnosis, disease management, guidelines Food allergy is an immune-based disease that has become a serious health concern in the United States. A recent study1 estimates that food allergy affects 5% of children under the age of 5 years and
4% of teens and adults, and its prevalence appears to be on the increase. The symptoms of this disease can range from mild to severe and, in rare cases, can lead to anaphylaxis, a severe and potentially life-threatening allergic reaction. There are no therapies available to prevent or treat food allergy: the only prevention option for the patient is to avoid the food allergen, and treatment involves the management of symptoms as they appear. And because the most common food allergens―eggs, milk,
peanuts, tree nuts, soy, wheat, crustacean shellfish, and fish―are highly prevalent in the US diet, patients and their families must remain constantly vigilant. The development of the Guidelines for the Diagnosis and Management of Food Allergy in the United States began in 2008 to meet a long-standing need for harmonization of best clinical practices related to food allergy across medical specialties. The resulting Guidelines reflect considerable effort by a wide range of
participants to establish consensus and consistency in definitions, diagnostic criteria, and management practices. They provide concise recommendations on how to diagnose and manage food allergy and treat acute food allergy reactions. In addition, they provide guidance on addressing points of controversy in patient management and also identify gaps in our current knowledge, which will help focus the direction of future research in this area. The Guidelines were developed over a
2-year period through the combined efforts of an Expert Panel and Coordinating Committee representing 34 professional organizations, federal agencies, and patient advocacy groups. The Expert Panel drafted the Guidelines using an independent, systematic literature review and evidence report on the state of the science in food allergy, as well as their expert clinical opinion. The National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH),
provided funding for this project and played a pivotal role as organizer and “honest broker” of the Guidelines project. As the lead NIH institute for research on food allergy, NIAID is deeply committed to improving the lives of patients with food allergy and is proud to have been involved in the development of these Guidelines. As our basic understanding of the human immune system and food allergy in particular increases, we hope to translate this information into improved clinical
applications. Although there are many challenges, the potential benefit for human health will be extraordinary. Food allergy (FA) is an important public health problem that affects adults and children and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for FA: the disease can only be managed by allergen
avoidance or treatment of symptoms. Moreover, the diagnosis of FA may be problematic, given that nonallergic food reactions, such as food intolerance, are frequently confused with FAs. Additional concerns relate to the differences in the diagnosis and management of FA in different clinical practice settings. Due to these concerns, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, working with more than 30 professional
organizations, federal agencies, and patient advocacy groups, led the development of “best practice” clinical guidelines for the diagnosis and management of FA (henceforth referred to as the Guidelines). Based on a comprehensive review and objective evaluation of the recent scientific and clinical literature on FA, the Guidelines were developed by and designed for allergists/immunologists, clinical researchers, and practitioners in the areas of pediatrics, family medicine, internal medicine,
dermatology, gastroenterology, emergency medicine, pulmonary and critical care medicine, and others. The Guidelines focus on diseases that are defined as FA (see section 2.1) and include both IgE-mediated reactions to food and some non-IgE-mediated reactions to food. The Guidelines do not discuss celiac disease, which is an immunologic non-IgE-mediated reaction to certain foods. Although this is an immune-based disease involving food, existing clinical guidelines for celiac disease
will not be restated here.2,3 In summary, the Guidelines: Provide concise recommendations (guidelines numbered 1 through 43) to a wide variety of health care professionals on how to diagnose FA, manage ongoing FA,
and treat acute FA reactions Identify gaps in the current scientific knowledge to be addressed through future research Identify and provide guidance on points of current controversy in patient management A companion Summary of the NIAID-Sponsored Expert Panel Report has been prepared from the Guidelines. This Summary contains all 43 recommendations, all “In summary” statements, definitions (section 1.3.5), 1 diagnostic table for FA, and 1
summary table for the pharmacologic management of anaphylaxis. It does not contain background information, supporting evidence for the recommendations and “In summary” statements, and other summary tables of data. The Summary is not intended to be the sole source of guidance for the health care professional, who should consult the Guidelines for complete information. Finally, these Guidelines do not address the management of patients with FA outside of clinical care settings (for
example, schools and restaurants) or the related public health policy issues. These issues are beyond the scope of this document. Other organizations have recently developed, or are currently developing, guidelines for FA. The European Academy of Allergy and Clinical Immunology (EAACI) has created a task force that is currently developing guidelines for the
diagnosis and management of FA. The model for development of guidelines by this task force is very similar to that used to generate these US Guidelines. Following completion of the EAACI guidelines, additional efforts will be made to harmonize the US Guidelines with the EAACI guidelines. Clinical practice guidelines on FA in children and young people are being developed for use in the National Health Service in England, Wales, and Northern Ireland by the National Institute for
Health and Clinical Excellence (NICE). These guidelines are intended for use predominantly in primary care and community settings. The model used for development of the NICE guidelines is also very similar to that used to generate the EAACI and US Guidelines. It is expected that NICE will release the final guidelines in early 2011. In 2008, the World Allergy Organization (WAO) Special Committee on Food Allergy identified cow's milk allergy (CMA) as a topic that would benefit from
a reappraisal of the more recent literature and an updating of existing guidelines, which summarized the achievements of the preceding decade and dealt mainly with prevention. It is in this context that the WAO Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) was created.4 The evidence-based DRACMA guidelines cover diagnostic algorithms,
challenge-testing methodology, consideration of appropriate sensitization tests, and the limitations of diagnostic procedures for CMA. In addition, there is discussion of appropriate substitute feeding formulas that can be used in various clinical situations, with consideration, for example, of patient preferences, costs, and local availability. In 2006, an FA practice parameter was published by a task force established by the American College of Allergy, Asthma and Immunology,
the American Academy of Allergy, Asthma, and Immunology, and the Joint Council of Allergy, Asthma and Immunology.5 The document, Food Allergy: A Practice Parameter, has been an outstanding resource for the allergy and immunology clinical community, but may not have had broad impact outside of this community. Notably, the new US
Guidelines are specifically aimed at all health care professionals who care for adult and pediatric patients with FA and related comorbidities. Thus, it is hoped that these Guidelines will have broad impact and benefit for all health care professionals. NIAID established a Coordinating Committee (CC), whose members are listed in
Appendix A, to oversee the development of the Guidelines; review drafts of the Guidelines for accuracy, practicality, clarity, and broad utility of the recommendations in clinical practice; review the final Guidelines; and disseminate the Guidelines. The CC members were from 34 professional organizations, advocacy groups, and federal agencies, and each member was vetted for financial conflict of
interest (COI) by NIAID staff. Potential COIs were posted on the NIAID Web site at http://www.niaid.nih.gov/topics/foodAllergy/clinical/Pages/FinancialDisclosure.aspx. The CC convened an Expert Panel (EP) in March 2009 that was chaired by Joshua Boyce, MD (Brigham and Women's Hospital, Boston, Mass). Panel members were specialists from a variety of relevant clinical, scientific, and public health areas (see Appendix B). Each member was vetted for financial COI by NIAID staff and approved by the CC. Potential COIs were posted on the NIAID Web site
provided in section 1.3.1. The charge to the EP was to use an independent, systematic literature review (see section 1.3.3), in conjunction with consensus expert opinion and EP-identified supplementary documents, to develop Guidelines that provide a comprehensive approach for diagnosing and managing FA based on the current state of the science. The EP organized the Guidelines into 5 major topic areas: Definitions, prevalence, and epidemiology
of FA (section 2) Natural history of FA and associated disorders (section 3) Diagnosis of FA (section 4) Management of nonacute food-induced allergic reactions and prevention of FA (section 5) Diagnosis and management of food-induced anaphylaxis and other acute allergic reactions to foods (section 6) Subtopics were developed for each of these 5 broad topic areas. RAND Corporation prepared an independent, systematic literature review and evidence report on the state of the science in FA. RAND had responded to the NIAID Request for Proposal AI2008035, Systematic Literature Review and Evidence Based Report on Food Allergy, and was subsequently awarded the contract in September 2008. The contract's principal investigator was Paul G. Shekelle, MD, PhD, an internationally recognized expert
in the fields of practice guidelines and meta-analysis. NIAID and the EP developed an extensive set of key questions,6 which were further refined in discussions with RAND. Literature searches were performed on PubMed, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and the World
Allergy Organization Journal, a relevant journal that is not included in PubMed. In most cases, searches were limited to the years 1988 (January) to 2009 (September), with no language restrictions. Additional publications identified by the EP and others involved in the review process also were included in the RAND review if and only if they met the RAND criteria for inclusion. RAND researchers screened all titles found through searches, as well as those that were submitted by
the EP or NIAID. Screening criteria were established to facilitate the identification of articles concerning definitions, diagnoses, prevention, treatment, management, and other topics. Articles were included or excluded based on article type and study purpose as follows: Article type Included: Original research or systematic reviews Excluded: Background or contextual reviews; nonsystematic reviews; commentary; other
types of articles Study purpose
RAND screened more than 12,300 titles, reviewed more than 1,200 articles, abstracted nearly 900 articles, and included 348 articles in the final RAND report. Two RAND investigators independently reviewed all titles and abstracts to identify potentially relevant articles. Articles that met the inclusion criteria were independently abstracted by a single RAND investigator. Because of the large number of articles and the short time for the review, articles were not independently abstracted by 2 RAND investigators (dual-abstracted). However, team members worked together closely and data were double-checked. Selected conclusions from the report have been published in a peer-reviewed journal,7 and the full version of the report with a complete list of references is available at http://www.rand.org/pubs/working_papers/WR757-1/. 1.3.4. Assessing the quality of the body of evidenceFor each key question, in addition to assessing the quality of each of the included studies, RAND assessed the quality of the body of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach,8 which was developed in 2004. GRADE provides a comprehensive and transparent methodology to develop recommendations for the diagnosis, treatment, and management of patients. In assessing the body of evidence, GRADE considers study design and other factors, such as the precision, consistency, and directness of the data. Using this approach, GRADE then provides a grade for the quality of the body of evidence. Based on the available scientific literature on FA, which in some areas was minimal, RAND used the GRADE approach to assess the overall quality of evidence for each key question assigned by the EP and assigned a grade according to the following criteria:9,10
A GRADE designation of “Low” for the quality of evidence does not imply that an article is not factually correct or lacks scientific merit. For example, a perfectly designed and executed study of a treatment in a small sample that is from a single site of highly selected patients might still yield an overall GRADE of “Low.” This is because a single small study is characterized as “sparse” data, and the patient population may not be representative of the larger population of patients with FA. Each of these factors reduces the level of evidence from “High,” which is how randomized controlled trial (RCT) evidence is designated initially. It is worth emphasizing that these 2 limitations are not of the study per se, but of the body of evidence. Replication of the study's result on other populations would result in a GRADE of “High.” It should be noted that the EP recommendations made in these Guidelines are often based on a GRADE classification of the quality of evidence as “Low,” thus necessitating more contribution to the recommendation from expert opinion. For additional information to understand the concept of “quality of the body of evidence,” please see Appendix C. 1.3.5. Preparation of draft Guidelines and Expert Panel deliberationsThe EP prepared a draft version of the Guidelines based on the RAND evidence report and also supplementary documents that were identified by the EP but not included in the RAND report. The supplementary documents contained information of significant value that was not included in the systematic literature review due to the objective criteria for inclusion or exclusion established by RAND, such as limits on demographics, study population size, and study design. The EP used this additional information only to clarify and refine conclusions drawn from sources in the systematic literature review. These documents are denoted with an asterisk (*) in Section 7: References. It also should be noted that included references are illustrative of the data and conclusions discussed in each section, and do not represent the totality of relevant references. For a full list of relevant references, the reader should refer to the full version of the RAND report. In October 2009, the EP discussed the first written draft version of the Guidelines and their recommendations. Following the meeting, the EP incorporated any panel-wide changes to the recommendations within the draft Guidelines. These revised recommendations were then subject to an initial panel-wide vote to identify where panel agreement was less than 90%. Controversial recommendations were discussed via teleconference and e-mail to achieve group consensus. Following discussion and revision as necessary, a second vote was held. All recommendations that received 90% or higher agreement were included in the draft Guidelines for public review and comment. In addition to the 43 recommendations, sections 3, 5, and 6 of the Guidelines contain “In summary” statements. These statements are intended to provide health care professionals with significant information that did not warrant a recommendation, or are in place of a recommendation when the EP or the CC could not reach consensus. All “In summary” statements received 90% or higher agreement. 1.3.6. Public comment period and draft Guidelines revisionThe draft Guidelines were posted to the NIAID Web site in February 2010 for a period of 60 days to allow for public review and comment. More than 550 comments were collected and reviewed by the CC, the EP, and NIAID. The EP revised the Guidelines in response to some of these comments. Further deliberation between the CC and the EP resulted in the revision of 5 recommendations. In addition, section 5.1.11, which discusses vaccination in patients with allergy to hen's egg (henceforth referred to as egg), also underwent substantial revision to bring it into better alignment with national vaccine policies. Consequently, the EP developed 1 recommendation for vaccination with MMR and MMRV, and 3 “In summary” statements for influenza, yellow fever, and rabies vaccinations. All new recommendations and “In summary” statements were subjected to a panel-wide vote and achieved 90% consensus or more. The final Guidelines were reviewed by the CC. 1.3.7. Dissemination of the final GuidelinesThe final Guidelines were published and made publically available via the Internet. 1.4. Defining the strength of each clinical guidelineThe EP has used the verb “recommends” or “suggests” in each clinical guideline. These words convey the strength of the guideline, defined as follows:
1.5. SummaryThe Guidelines present 43 recommendations by an independent EP for the diagnosis and management of FA and food-induced anaphylaxis. Three “In summary” statements provide a brief review of US national vaccine policy specifically related to vaccination of patients with egg allergy. The Guidelines are intended to assist health care professionals in making appropriate decisions about patient care in the United States. The recommendations are not fixed protocols that must be followed. Health care professionals should take these Guidelines into account when exercising their clinical judgment. However, this guidance does not override their responsibility to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient, guardian, or caregiver. Clinical judgment on the management of individual patients remains paramount. Health care professionals, patients, and their families need to develop individual treatment plans that are tailored to the specific needs and circumstances of the patient. This document is intended as a resource to guide clinical practice and develop educational materials for patients, their families, and the public. It is not an official regulatory document of any government agency. 2. Definitions, Prevalence, and Epidemiology of Food Allergy2.1. Definitions2.1.1. Definitions of food allergy, food, and food allergensThe EP came to consensus on definitions used throughout the Guidelines. A food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. A food is defined as any substance—whether processed, semiprocessed, or raw—that is intended for human consumption, and includes drinks, chewing gum, food additives, and dietary supplements. Substances used only as drugs, tobacco products, and cosmetics (such as lip-care products) that may be ingested are not included. Food allergens are defined as those specific components of food or ingredients within food (typically proteins, but sometimes also chemical haptens) that are recognized by allergen-specific immune cells and elicit specific immunologic reactions, resulting in characteristic symptoms. Some allergens (most often from fruits and vegetables) cause allergic reactions primarily if eaten when raw. However, most food allergens can still cause reactions even after they have been cooked or have undergone digestion in the stomach and intestines. A phenomenon called cross-reactivity may occur when an antibody reacts not only with the original allergen, but also with a similar allergen. In FA, cross-reactivity occurs when a food allergen shares structural or sequence similarity with a different food allergen or aeroallergen, which may then trigger an adverse reaction similar to that triggered by the original food allergen. Cross-reactivity is common, for example, among different shellfish and different tree nuts. (See Appendix D, Table S-I.) Food oils—such as soy, corn, peanut, and sesame—range from very low allergenicity (if virtually all of the food protein is removed in processing) to very high allergenicity (if little of the food protein is removed in processing). 2.1.2. Definitions of related termsThe terms allergy and allergic disease are broadly encompassing and include clinical conditions associated with altered immunologic reactivity that may be either IgE mediated or non-IgE mediated. IgE is a unique class of immunoglobulin that mediates an immediate allergic reaction. The term food hypersensitivity also is often used to describe FA, although other groups have used this term more broadly to describe all other food reactions, including food intolerances. In these Guidelines, the EP has refrained from using the term food hypersensitivity except for the term immediate gastrointestinal (GI) hypersensitivity, which is IgE mediated. Because individuals can develop allergic sensitization (as evidenced by the presence of allergen-specific IgE (sIgE)) to food allergens without having clinical symptoms on exposure to those foods, an sIgE-mediated FA requires both the presence of sensitization and the development of specific signs and symptoms on exposure to that food. Sensitization alone is not sufficient to define FA. Although FA is most often caused by sIgE-mediated reactions to food, the EP also considered literature relevant to reactions likely mediated by immunologic but non-IgE-induced mechanisms, including food protein-induced enteropathy, exacerbations of eosinophilic GI disorders (EGIDs) (eosinophilic gastritis, eosinophilic enteritis, eosinophilic colitis, and eosinophilic gastroenteritis), and food-induced allergic contact dermatitis. In these conditions, sensitization to food protein cannot be demonstrated based on sIgE. The diagnosis of non-IgE-mediated FA is based on signs and symptoms occurring reproducibly on exposure to food, resolution of those signs and symptoms with specific food avoidance, and, most often, histologic evidence of an immunologically mediated process, such as eosinophilic inflammation of the GI tract. These Guidelines generally use the term tolerate to denote a condition where an individual has either naturally outgrown an FA or has received therapy and no longer develops clinical symptoms following ingestion of the food. This ability to tolerate food does not distinguish 2 possible clinical states. Individuals may tolerate food only for a short term, perhaps because they have been desensitized by exposure to the food. Alternatively, they may develop long-term tolerance. The specific term tolerance is used in these Guidelines to mean that an individual is symptom free after consumption of the food or upon oral food challenge weeks, months, or even years after the cessation of treatment. The immunological mechanisms that underlie tolerance in humans are poorly understood. Although many different foods and food components have been recognized as food allergens,11 these Guidelines focus on only those foods that are responsible for the majority of observed adverse allergic or immunologic reactions. Moreover, foods or food components that elicit reproducible adverse reactions but do not have established or likely immunologic mechanisms are not considered food allergens. Instead, these non-immunologic adverse reactions are termed food intolerances. For example, an individual may be allergic to cow's milk (henceforth referred to as milk) due to an immunologic response to milk protein, or alternatively, that individual may be intolerant to milk due to an inability to digest the sugar lactose. In the former situation, milk protein is considered an allergen because it triggers an adverse immunologic reaction. Inability to digest lactose leads to excess fluid production in the GI tract, resulting in abdominal pain and diarrhea. This condition is termed lactose intolerance, and lactose is not an allergen because the response is not immune based. Note: The words tolerance and intolerance are unrelated terms, even though the spelling of the words implies that they are opposites. Adverse reactions to food can therefore best be categorized as those involving immune-mediated or non-immune-mediated mechanisms, as summarized in Fig 1.  Types of adverse reactions to food Non-immune mediated reactions or food intolerances include metabolic, pharmacologic, toxic, and undefined mechanisms. In some cases, these reactions may mimic reactions typical of an immunologic response. It is therefore important to keep these food components or mechanisms in mind when evaluating adverse food reactions. Most adverse reactions to food additives, such as artificial colors (for example, FD&C yellow 5 [tartrazine]) and various preservatives (for example, sulfites), have no defined immunologic mechanisms. These food components, as well as other foods contributing to food intolerances, are not specifically discussed in these Guidelines. 2.1.3. Definitions of specific food-induced allergic conditionsA number of specific clinical syndromes may occur as a result of FA, and their definitions are as follows: Food-induced anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.12,13 Typically, IgE-mediated food-induced anaphylaxis is believed to involve systemic mediator release from sensitized mast cells and basophils. In some cases, such as food-dependent, exercise-induced anaphylaxis, the ability to induce reactions depends on the temporal association between food consumption and exercise, usually within 2 hours. GI food allergies include a spectrum of disorders that result from adverse immunologic responses to dietary antigens. Although significant overlap may exist between these conditions, several specific syndromes have been described. These are defined as follows:
Cutaneous reactions to foods are some of the most common presentations of FA and include IgE-mediated (urticaria, angioedema, flushing, pruritus), cell-mediated (contact dermatitis, dermatitis herpetiformis), and mixed IgE- and cell-mediated (atopic dermatitis) reactions. These are defined as follows:
Respiratory manifestations of IgE-mediated FA occur frequently during systemic allergic reactions and are an important indicator of severe anaphylaxis.26 However, FA is an uncommon cause of isolated respiratory symptoms, namely those of rhinitis and asthma. Heiner syndrome is a rare disease in infants and young children. Caused primarily by the ingestion of milk, it is characterized by chronic or recurrent lower respiratory symptoms often associated with:27,28
The syndrome is associated with non-IgE-mediated immune responses, such as precipitating antibodies to milk protein fractions. Evidence often exists of peripheral eosinophilia, iron deficiency, and deposits of immunoglobulins and C3 in lung biopsies in some cases. Milk elimination leads to marked improvement in symptoms within days and clearing of pulmonary infiltrates within weeks.28 The immunopathogenesis of this disorder is not understood, but seems to combine cellular and immune-complex reactions, causing alveolar vasculitis. In severe cases, alveolar bleeding leads to pulmonary hemosiderosis. There is no evidence for involvement of milk-specific IgE in this disease. 2.2. Prevalence and epidemiology of food allergyThe true prevalence of FA has been difficult to establish for several reasons.
These Guidelines do not exclude studies based on the diagnostic criteria used, but the results must be viewed critically based on these diagnostic differences. In addition, prevalence and incidence studies from the United States and Canada are the focus of these Guidelines, but key studies from elsewhere also are included. 2.2.1. Systematic reviews of the prevalence of food allergyOne meta-analysis30 and 1 systematic review31 of the literature on the prevalence of FA have recently been published. The meta-analysis by Rona et al,30 which includes data from 51 publications, stratifies to children and adults and provides separate analyses for the prevalence of FA for 5 foods: milk, egg, peanut, fish, and crustacean shellfish. As shown in Table I, the investigators report an overall prevalence of self-reported FA of 12% and 13% for children and adults, respectively, to any of these 5 foods. This compares to a much lower value of 3% for adults and children combined when assessed by self-reported symptoms plus sensitization or by double-blind, placebo-controlled food challenge (DBPCFC). These data emphasize the fact that FAs are over-reported by patients and that objective measurements are necessary to establish a true FA diagnosis. For specific foods, results for all ages show that prevalence is highest for milk (3% by symptoms alone, 0.6% by symptoms plus positive skin prick test (SPT), and 0.9% by food challenge). Table IPrevalence of allergy to peanut, milk, egg, fish, and crustacean shellfish30
The systematic review by Zuidmeer et al,31 which includes data from 33 publications, presents an epidemiological data review of allergy to fruits, vegetables/nonpeanut legumes, tree nuts, wheat, and soy. The results, summarized in Table II, demonstrate that the reported prevalence for these foods is generally lower than for the 5 foods reported in Table I. Once again, the prevalence of FA is much higher when assessed using self-reporting than when using sensitization or food challenge. Table IIPrevalence of allergy to fruits, vegetables/nonpeanut legumes, tree nuts, wheat, and soy31
Two additional studies1,32 also provide US prevalence data on FA. In data obtained via proxy that reported on FA from the National Health Interview Survey in 2007, the Centers for Disease Control and Prevention (CDC) found that approximately 3 million children under age 18 years (3.9%) reported an FA in the previous 12 months. In addition, from 2004 to 2006, there was an increase from approximately 2,000 to 10,000 hospital discharges per year of children under age 18 years with a diagnosis related to FA.1 Another US study analyzed national data from the Infant Feeding Practices Study II, a longitudinal mail survey from 2005 to 2007 of women who gave birth to a healthy single child after a pregnancy of at least 35 weeks. The survey began in the third trimester of pregnancy and continued periodically thereafter up to age 1 of the infant.32 In this analysis, probable FA was defined either as a doctor-diagnosed FA or as the presence of food-related symptoms (ie, swollen eyes, swollen lips, or hives). Of 2,441 mothers, 60% completed all serial questionnaires with detailed questions about problems with food. About 500 infants were characterized as having a food-related problem, and 143 (6%) were classified as probable FA cases by 1 year of age. 2.2.2. Prevalence of allergy to specific foods, food-induced anaphylaxis, and food allergy with comorbid conditionsPeanut and tree nut allergyInvestigators from the United States and several other countries have published prevalence rates for allergy to peanut and tree nuts. The results, which are presented in Appendix D, Tables S-II and S-III, include sensitization rates and other clinical results. Where prevalence and sensitization are measured in the same study, prevalence is always less than sensitization. Peanut summary
Tree nut summary
Seafood allergySicherer et al33 used random calling by telephone of a US sample to estimate the lifetime prevalence rate for reported seafood allergy.
Milk and egg allergyTwo European studies have examined the prevalence of milk and egg allergy. In a Danish cohort of 1,749 children followed from birth through age 3, children were evaluated by history, milk elimination, oral food challenge, and SPTs or sIgE.34
In a Norwegian cohort of 3,623 children followed from birth until age 2, parents completed questionnaires regarding adverse food reactions at 6-month intervals.
Food-induced anaphylaxisFive US studies assessed the incidence of anaphylaxis related to food; all used administrative databases or medical record review to identify cases of anaphylaxis.38-42 These studies found wide differences in the rates (from 1/100,000 population to as high as 70/100,000 population) of hospitalization or emergency department visits for anaphylaxis, as assessed by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes or medical record review. These variations may be due to differences in the study methods or differences in the populations (Florida, New York, Minnesota). The proportion of anaphylaxis cases thought to be due to foods also varied between 13% and 65%, with the lowest percentages found in studies that used more stringent diagnostic criteria for anaphylaxis. One study reported that the number of hospitalizations for anaphylaxis increased with increasing age, while another study reported that total cases of anaphylaxis were almost twice as high in children as in adults. The EP agreed that any estimate of the overall US incidence of anaphylaxis is unlikely to have utility because such an estimate fails to reflect the substantial variability in patient age, geographic distribution, criteria used to diagnose anaphylaxis, and the study methods used. Food allergy with comorbid conditionsAccording to a recent CDC study, children with FA are about 2 to 4 times more likely to have other related conditions such as asthma (4.0 fold), AD (2.4 fold), and respiratory allergies (3.6 fold), compared with children without FA.1 Several studies report on the co-occurrence of other allergic conditions in patients with FA,43-45 such as:
In patients with both AD and FA:46
The prevalence of FA in individuals with moderate to severe AD is 30% to 40%, and these patients have clinically significant IgE-mediated FA (as assessed by some combination of convincing symptoms, SPTs, sIgE levels, or oral food challenges)47 or a definite history of immediate reactions to food.48 A retrospective review of the records of 201 children with an ICD-9 diagnosis of asthma found that 44% (88 of 201) have concomitant FA.49 Thus, children with FA may be especially likely to develop other allergic diseases. However, the above studies should be interpreted with caution, since they may be subject to selection bias. 2.3. Knowledge gapsStudies on the incidence, prevalence, and epidemiology of FA are lacking, especially in the United States. It is essential that studies using consistent and appropriate diagnostic criteria be initiated to understand the incidence, prevalence, natural history, and temporal trends of FA and associated conditions. A recent example of a comprehensive approach to assessing the prevalence, health care costs, and basis for FA in Europe is the EuroPrevall project (http://www.europrevall.org). This European Union-supported effort has focused on characterizing the patterns and prevalence of FA in infants, children, and adults across 24 countries. The project also has investigated the impact that FA has on the quality of life and associated economic costs. EuroPrevall data have already revealed an unexpected diversity in the variety of foods to which Europeans are allergic, as well as the prevalence of FA across relatively small geographic distances. Given the size and diversity of the US population, it is likely that using a similar approach could yield important information about FA in the United States. 3. Natural History of Food Allergy and Associated DisordersThe EP reviewed the literature on the natural history of FA and summarized the available data for the most common food allergens in the United States: egg, milk, peanut, tree nuts, wheat, crustacean shellfish, and soy. Natural history data for fish allergy were unavailable as of the completion of the systematic literature review (September 2009). In addition, the EP sought to:
It should be noted that published studies from the United States or Canada addressing the natural history of FA typically come from selected populations (for example, from a single clinic or hospital) that may not be representative of the general or community-based patient population with a specific FA condition. Thus, the findings of these studies may not necessarily be extrapolated to all patients with the condition. 3.1. Natural history of food allergy in childrenIn summary: Most children with FA eventually will tolerate milk, egg, soy, and wheat; far fewer will eventually tolerate tree nuts and peanut. The time course of FA resolution in children varies by food and may occur as late as the teenage years. A high initial level of sIgE against a food is associated with a lower rate of resolution of clinical allergy over time. An important part of the natural history of FA is determining the likelihood and the actual time of resolution of the FA.
Because the natural history of FA varies by the food, the natural history of each of the most common FAs for which data are available is addressed below. 3.1.1. EggNumerous studies, such as 1 from Sweden50 and 1 from Spain,51 indicate that most infants with egg allergy become tolerant to egg at a young age. An estimated 66% of children became tolerant by age 7 in both studies. In a retrospective review52 of 4,958 patient records from a university allergy practice in the United States, the rate of egg allergy resolution was slower than in the studies mentioned above.
3.1.2. Milk
3.1.3. PeanutSeveral US studies, all involving selected populations from specialist clinics, provide data for the natural history of peanut allergy.44,55-60 (Table III presents a summary of results from some of these studies.) In most of the studies, patients were diagnosed based on history, except in 1 study,44 where 33% of the patients were diagnosed based on SPTs and sIgE to peanut. These studies examined the development of tolerance and found that a small percentage of children tolerated peanut several years after their initial diagnoses. Table IIISummary of US studies of the natural history of peanut allergy in children
In a study of the recurrence of peanut allergy after the development of apparent tolerance,58 68 children (median age at diagnosis 1.1 years) who had outgrown peanut allergy were evaluated (median age at evaluation 8.5 years). The results showed:
3.1.4. Tree nutsIn a US evaluation61 of 278 patients with positive tree nuts sIgE:
3.1.5. WheatIn a US study62 of 103 patients with wheat allergy (IgE mediated, not celiac disease), rates of resolution were:
Higher wheat sIgE levels were associated with poorer outcomes. The peak wheat sIgE level recorded was a useful predictor of persistent allergy (p < 0.001), although many children with even the highest levels of wheat sIgE outgrew their allergy to wheat. The median age of resolution of wheat allergy was approximately 6.5 years in this population. In a significant minority of patients, wheat allergy persisted into adolescence. 3.1.6. Crustacean shellfishFew studies have systematically assessed the natural history of allergy to crustacean shellfish, which commonly has onset in adult life. In 1 US study,63 25 sera were collected sequentially during a 24-month interval from 11 individuals, each with a clinical history suggesting allergy to shrimp, and 10 control individuals. The sera were evaluated for shrimp sIgE. Of the 11 individuals with suggestive histories and positive sIgE who underwent DBPCFC to shrimp:
3.1.7. SoyIn a retrospective review64 of US patients with soy allergy seen in a tertiary referral clinic, 133 patients were studied (96 male and 37 female patients). The median age at the initial visit was 1 year (ranging from 2 months to 17.5 years); the median duration of follow-up was 5 years (ranging from 1 to 19 years). Kaplan-Meier analysis predicted resolution of soy allergy in:
By age 6, tolerance to soy developed in:
These data demonstrate that absolute soy sIgE levels are useful predictors of developing tolerance to soy. 3.2. Natural history of levels of allergen-specific IgE to foods in childrenIn summary: For many patients, sIgE antibodies to foods appear within the first 2 years of life. Levels may increase or decrease; a decrease is often associated with the ability to tolerate the foods. Based on the previously discussed studies pertaining to individual foods (section 3.1), sIgE to a food commonly appears within the first 2 years of life, with the levels increasing or decreasing over time depending on the food. In a study54 of patients with allergy to egg and milk who had repeated DBPCFC, sIgE levels to egg and milk were retrospectively determined from stored serum samples obtained at the time of the food challenges.
3.3. Natural history of food allergy in adultsIn summary: FA in adults can reflect persistence of pediatric FAs (for example, milk, peanut, and tree nuts) or de novo sensitization to food allergens encountered after childhood. Although there is a paucity of data from US studies, FA that starts in adult life tends to persist. In a retrospective study65 of anaphylaxis in 601 patients with a mean age of 37 years (ranging from 1 to 79 years), 22% (133) of cases were food-related. The causative foods in descending order of frequency were crustacean shellfish, peanut, food additives or spices, tree nuts, beef, almond, and peach. In this study, however, it should be noted that anaphylaxis was used as a surrogate for the incidence of FA as measured by oral food challenge and includes non-life-threatening, and largely cutaneous, reactions. A non-US study66 compared 30 adults with milk allergy to 25 control individuals who were milk-sensitized but tolerant. The investigators found that:
The foods widely recognized to cause IgE-mediated FA in young children are, in order of prevalence, milk, egg, peanut, tree nuts, fish, and crustacean shellfish, followed by wheat and soy. Allergy to milk, egg, wheat, and soy generally resolves, thus becoming less prevalent in adults. In contrast, allergy to peanut and tree nuts is more likely to persist.15 Allergy to crustacean shellfish, which most commonly develops in adulthood, is a relatively common allergy in adulthood, and usually persists.30,33 3.4. Natural history of conditions that coexist with food allergyIn summary: FA may coexist with asthma, AD, EoE, and exercise-induced anaphylaxis. In patients with asthma, the coexistence of FA may be a risk factor for severe asthma exacerbations. Moreover, food may be a trigger for exercise-induced anaphylaxis. Elimination of food allergens in sensitized individuals can improve symptoms of some comorbid conditions. 3.4.1. AsthmaIn summary: Asthma and FA often coexist in pediatric and adult patients. FA is associated with severe asthma. Four US studies67-70 assessed the relationship of FA to asthma. These studies drew several conclusions:
Two other studies71,72 dealing with fatal or near-fatal anaphylaxis due to foods in US children reported that all or almost all patients who died also had asthma. Furthermore, as already noted in numerous studies, concomitant asthma is highly prevalent among patients diagnosed with FA. Although the EP did not find evidence for a causal link, the coexistence of FA and asthma is a risk factor for asthma exacerbations. Moreover, a high prevalence of asthma is reported among deaths from anaphylaxis due to food. 3.4.2. Atopic dermatitisIn summary: AD and FA are highly associated. When tolerance develops to a food, the reintroduction of the food in the diet will not result in recurrence or worsening of the AD. Up to 37% of children under 5 years of age with moderate to severe AD will have IgE-mediated FA.47 Whether FA can exacerbate AD is still controversial, in part because the signs and symptoms of food allergen exposure are so pleomorphic and because well-designed relevant food allergen avoidance trials have rarely been done in patients with AD. A systematic review of 9 RCTs,73 which assessed the effects of dietary exclusions for the treatment of established AD in unselected patients, found little evidence to support the role for food avoidance. However, several studies74-76 found an improvement in pruritus when patients with egg allergy and AD were placed on an egg-free diet. In a US study46 of the natural history of FA in children with AD, 75 children with a mean age of 8 months (ranging from 3 to 18 months) were diagnosed using a DBPCFC.
All the children were placed on allergen-restricted diets, with a history of compliance of 90%. After 1 or 2 years, the patients underwent repeat food challenge tests.
3.4.3. Eosinophilic esophagitisIn summary: EoE is commonly associated with sensitization to foods. The natural history of EoE is that of a chronic condition that resolves spontaneously or with therapy, and then relapses. There are insufficient data to judge the impact of food sensitization on the natural history of EoE, and vice versa. Only retrospective data exist that support a beneficial effect of dietary changes on the histopathologic changes in the esophagus in EoE. Three US studies77-79 examined the natural history of EoE in children, and the results are presented in Appendix D, Table S-IV. Briefly:
Two other retrospective studies80,81 evaluated the effect of specific food elimination diets or elemental diets in treating EoE and found:
The influence of concomitant EoE on the natural history of FA is poorly understood. As discussed above, EoE is associated with a frequent sensitization to food allergens, as evidenced by the presence of sIgE by SPTs, or delayed reactions to food antigens by atopy patch tests (APTs). Patients who present with EoE often have either a medical history of, or ongoing, clinical FA. Food sensitization in patients with EoE is mainly against the most common food allergens, but sensitization to other uncommon food allergens, such as beans, peas, and mustard, is often detected. Some retrospective studies in children have shown that removal of the sensitizing foods may lead to resolution of EoE.79 The natural history of clinical FA in patients with EoE has not been well studied, but clinical experience suggests that it is the same as in patients with clinical FA without EoE. 3.4.4. Exercise-induced anaphylaxisIn summary: Exercise-induced anaphylaxis in adults is triggered by foods in about one third of patients and has a natural history marked by frequent recurrence of the episodes. There are no natural history studies of exercise-induced anaphylaxis in children. However, a US survey82 of 279 adult patients (aged 18 or older) from a single center between 1980 and 1993 examined the natural history of exercise-induced anaphylaxis and found that:
In most cases of exercise-induced anaphylaxis associated with food, the food can be ingested without symptoms in the absence of exercise. Although this study suggests a role for FA in the pathophysiology of exercise-induced anaphylaxis, the results must be interpreted cautiously since the diagnosis of FA was not based on objective testing. 3.4.5. Allergic rhinitisIgE-mediated FA does not commonly manifest as allergic rhinitis. Similarly, allergic rhinitis is not thought to be a risk factor for the development of FA.83 3.5. Risk factors for the development of food allergyIn summary: Family history of atopy and the presence of AD are risk factors for the development of both sensitization to food and confirmed FA. A family history of atopy is a risk factor for FA as well as all other atopic disorders, as illustrated by the following 3 studies:
These studies strongly suggest that FA and moderate to severe AD occur frequently in the same child and that early-onset severe AD is associated with risk for sensitization to food. The mechanism of early sensitization to foods is unclear. A recent study85 has suggested that peanut sensitization is independently associated with:
3.6. Risk factors for severity of allergic reactions to foodsIn summary: The severity of allergic reactions to foods is multifactorial and variable.67,71,72,86,87 The severity of a reaction cannot be accurately predicted by the degree of severity of past reactions nor by the level of sIgE or the size of the SPT wheal. The factor most commonly identified with the most severe reactions is the coexistence of asthma. The severity of allergic reactions to food varies based on:
The severity also may be influenced by:
Some patients who have had near-fatal or fatal reactions also had 1 or more of the following:
3.7. Incidence, prevalence, and consequences of unintentional exposure to food allergensIn summary: Self-reported reactions to food frequently occur in patients with a known diagnosis of FA. Although a subset of these reactions is due to intentional exposure, most are due to unintentional exposure. Both types of exposure can be life-threatening. There is no evidence that unintentional or intentional exposures to the food allergen alter the natural history of the FA. Data on the incidence and prevalence of unintentional exposures to a food allergen and subsequent reactions are derived from several longitudinal studies of patients with individual FAs. In 1 study,55 83 children who had been diagnosed with clinical hypersensitivity to peanut prior to the age of 4 years were followed for 5 years. The nature and frequency of adverse reactions caused by accidental peanut exposure are shown in Fig 2. Briefly: The severity of the subsequent reactions to peanuts LTR, Life-threatening reaction.
A retrospective chart review study56 of pediatric patients with peanut allergy seen in a university practice between 2000 and 2006 found that unintentional ingestions occurred in 39% of 140 patients, with a mean of 1.8 unintentional ingestions per patient and a range of 1 to 10 ingestions. The median time to first unintentional ingestion was 12.5 months after diagnosis, and 25% of patients reported a subsequent reaction that was more severe than the first. A telephone survey88 about unintentional exposures to peanuts in 252 children found that 35 unintentional exposures occurred in 29 children over a period of 244 patient-years, yielding an annual incidence rate of 14.3%. Of interest, 85% of these children attended schools prohibiting peanuts. A survey study89 of university students with FA found that 44% (122 of 278) reported having had a reaction to a food while enrolled in the university and 27% (76 of 278) had the reaction while on campus. When the students provided the locations where reactions occurred (could be multiple locations), the results were: restaurant (21.3%), residence hall (19.9%), parent's house (18.8%), apartment (17.1%), friend's house (16.7%), dining hall (13.6%), and other (5%). 3.8. Knowledge gapsMany gaps exist in the published literature on the natural history of FA. In particular, although there are several follow-up studies from single clinics, there are no data from community-based populations in the United States. Thus, the true natural history of symptoms, comorbid conditions, and the frequency and impact of inadvertent exposures are largely unknown. Little is known about:
No information is available on:
Other important areas that need to be addressed include:
4. Diagnosis of Food Allergy4.1. When should food allergy be suspected?Guideline 1: The EP recommends that FA should be considered:
Rationale: Sufficient evidence exists to support the evaluation of FA in patients presenting with specific allergic signs and symptoms following the ingestion of food or with certain disorders frequently associated with allergic reactions to food, even in some cases without an apparent relationship to eating. Balance of benefits and harms: Identification and avoidance of foods responsible for food-induced allergic reactions improve quality of life and potentially prevent life-threatening reactions and disorders. With the appropriate evaluation, there is a low risk of erroneously diagnosing someone as food allergic and adversely affecting his or her nutritional well-being and social interactions. Quality of evidence: Moderate Contribution of expert opinion: Significant When an individual presents with anaphylaxis or any combination of the symptoms listed in Table IV shortly after ingesting food, a diagnosis of FA should be considered, especially if symptoms have followed the ingestion of a specific food on more than 1 occasion. However, as mentioned in section 2.1.3, FA rarely causes isolated respiratory symptoms, namely those of rhinitis and asthma. Food-induced allergic reactions may be mediated only by IgE mechanisms, only by non-IgE-mediated mechanisms, or by both IgE- and non-IgE-mediated mechanisms. Furthermore, some diseases (for example, contact urticaria) can be mediated by either IgE- or non-IgE-mediated mechanisms. The diagnosis of IgE-mediated allergy is generally easier to make when tests for sIgE antibodies are positive. 4.1.1. Timing of food-induced allergic reactionsAllergic reactions to a food or food additive may present with a variety of symptoms (Table IV). These reactions may be:
4.1.2. IgE-mediated reactions to foodIgE-mediated reactions to foods are more common in young children, affecting up to 6% of children under 5 years old, and are more frequently seen in children with certain atopic disorders, such as AD. For example, 1 study found that approximately 35% of children with moderate to severe AD had FA.90 Another study found that the younger the child and the more severe the AD, the greater the likelihood that the child had an FA.91 Although any food may cause an allergic reaction, symptoms following the ingestion of certain foods should raise greater suspicion of FA, especially in atopic individuals. For example:
Symptoms of FA should occur consistently following the ingestion of the causative food allergen, although small, sub-threshold quantities of a food allergen or extensively baked, heat-denatured foods (for example, milk and egg) may sometimes be ingested without inducing symptoms. When evaluating older patients, certain complementary factors must be considered, such as exercise, alcohol consumption, and use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). Some individuals will only experience allergic reactions if they ingest specific foods in association with these factors. For example, anaphylaxis that occurs following exercise is associated with sensitization to specific foods in approximately 30% of cases.92 Sensitization to food proteins and allergic reactions to food are much more prevalent in individuals with certain clinical disorders. For example, more than 95% of a population consisting of children and adolescents with EoE experienced marked clinical and histological improvement when placed on a food elimination (often elemental) diet,93 although the causative role of IgE-mediated mechanisms in EoE is unclear. 4.1.3. Mixed IgE- and non-IgE-mediated reactions to foodMixed IgE- and non-IgE-mediated mechanisms should be suspected when symptoms, which generally involve the GI tract, are of a more chronic nature, do not resolve quickly, and are not closely associated with ingestion of an offending food. An example of such a disorder is EoE. Thus, the presence of FA should be suspected but the differential diagnosis will be broader as compared with IgE-mediated FA. FA should be suspected when the results of an esophageal biopsy―performed as part of an evaluation for chronic/intermittent symptoms of gastroesophageal reflux―reveal EoE, as evidenced by greater than 15-20 eosinophils per high-powered field on biopsy.17 EoE can be diagnosed at any age, but is most common in infants, children, and adolescents. In adults, symptoms of EoE include abdominal pain, dysphagia, and food impaction. Allergic eosinophilic gastroenteritis can manifest at any age and present as chronic abdominal pain, emesis, poor appetite, failure to thrive, weight loss, anemia, or protein-losing enteropathy. Although a single disease may have underlying pathophysiological mechanisms that involve both IgE-dependent and IgE-independent pathways (for example, EoE), some diseases can manifest in response to either IgE-dependent or IgE-independent triggers. An example is contact urticaria, which can be triggered by direct contact between the skin and offending food, but the symptoms may be IgE-mediated or non-IgE-mediated. 4.1.4. Differential diagnosis of food allergyIn a meta-analysis30 of studies evaluating the prevalence of FA, up to 35% of individuals reporting a reaction to food believe they have FA, whereas studies confirming FA by oral food challenge suggest a much lower prevalence of about 3.5%. Much of this discrepancy is due to a misclassification of adverse reactions to foods that are not allergic in origin, for example lactose intolerance causing bloating, abdominal pain, and diarrhea after consuming milk products. Many causes of reactions to foods are not allergic in origin. In the differential diagnosis of FAs, allergic disorders from other causes, such as drugs, as well as disorders that are not immunologic in nature, must be considered. The patient's medical history is vital in excluding these alternative diagnoses. For example:
4.2. Diagnosis of IgE-mediated food allergy4.2.1. Medical history and physical examinationGuideline 2: The EP recommends using medical history and physical examination to aid in the diagnosis of FA.
Rationale: Medical history is useful for identifying food allergens that may be responsible for IgE-mediated allergic reactions, but it lacks sufficient sensitivity and specificity to definitively make a diagnosis of FA. Moreover, medical history is more useful in diagnosing immediate food-induced allergic reactions compared with delayed reactions. Further evaluation, for example laboratory studies or oral food challenges, is required to confirm a diagnosis of FA. Balance of benefits and harms: The medical history and physical examination provide evidence for suspecting FA and focus the evaluation. However, basing the diagnosis of FA on either history or physical examination alone may lead to an erroneous diagnosis of FA and unnecessarily restrictive diets that could have adverse nutritional and social consequences. Quality of evidence: Low Contribution of expert opinion: Significant In evaluating a patient with suspected FA, a thorough medical history is very important in identifying symptoms associated with FA (Table IV) and focusing the diagnostic workup, but alone cannot be considered diagnostic.98,99 The nature of the reaction often suggests the underlying mechanism, either IgE mediated (immediate) or non-IgE mediated (delayed), and will determine the diagnostic tests to be used. Because none of the symptoms of FA are pathognomonic for the disorder, the medical history may be used to help identify causative allergens or to differentiate the reaction from nonallergic disorders, even though history alone does not provide sufficient sensitivity or specificity to make a diagnosis of FA.100 Critical questions should include the following:
No findings in a physical examination are diagnostic of FA. The presence of physical signs at the time of the physical examination may verify the diagnosis of an atopic disorder (for example, urticaria or AD) or suggest prolonged symptoms (for example, loss of body weight in patients with EoE). Physical examination also may reveal findings more suggestive of a nonallergic disorder that would require further investigation and testing. Guideline 3: The EP recommends that parent and patient reports of FA must be confirmed, because multiple studies demonstrate that 50% to 90% of presumed FAs are not allergies. Rationale: Given the low positive predictive value of self-reported symptoms, it is important that all suspected FA be confirmed by appropriate evaluation (for example, oral food challenge or tests for allergic sensitization). Balance of benefits and harms: Because unnecessary food avoidance affects quality of life and nutrition, there is possible harm in over-diagnosing FA. Quality of evidence: High Contribution of expert opinion: Minimal As described in section 2.2 (Tables I and II), 2 systematic reviews/meta-analyses found that the prevalence of FA based on self-reported symptoms of FA was several-fold higher compared with when the diagnosis was based on sensitization alone, sensitization with symptoms, or DBPCFC. 4.2.2. Methods to identify the causative foodWhen evaluating a patient for FA, the diagnostic tests selected are based on a comprehensive medical history. The history should suggest the possible allergic mechanism involved (ie, IgE mediated or non-IgE mediated), which then determines the types of testing to be pursued and the possible foods involved. Tests selected to evaluate FA should be based on the patient's medical history and not comprise large general panels of food allergens. In addition, diagnostic tests for nonallergic disorders may be needed, depending on the differential diagnosis.99 4.2.2.1. Skin prick testGuideline 4: The EP recommends performing an SPT (also known as a skin puncture test) to assist in the identification of foods that may be provoking IgE-mediated food-induced allergic reactions, but the SPT alone cannot be considered diagnostic of FA. Rationale: SPTs are safe and useful for identifying foods potentially provoking IgE-mediated food-induced allergic reactions, but they have a low positive predictive value for the clinical diagnosis of FA. Balance of benefits and harms: The reagents and methods for performing SPTs are not standardized. Nevertheless, SPTs effectively detect the presence of sIgE, but many patients have sIgE without clinical FA. Compared with oral food challenges, SPTs have low specificity and low positive predictive value for making an initial diagnosis of FA. Thus, use of SPTs in the clinical setting may lead to over-diagnosis. However, in a patient with confirmed FA, an SPT is valuable in identifying the food(s) responsible for IgE-mediated FA. In the clinical setting, when compared with oral food challenges, SPTs have high sensitivity and high negative predictive values. Quality of evidence: Moderate Contribution of expert opinion: Significant The results of an SPT are considered “immediate” because the wheal and flare develop typically within 30 minutes following injection of allergen. SPTs are the most commonly performed procedure in the evaluation of IgE-mediated FA.101-103 However, there are no standard reagents for SPT testing, and no international standards for administering the test and interpreting the results.101 A positive SPT is generally considered a wheal with a mean diameter 3 mm or greater than the negative control.102 Various studies use different methods to define a positive test, from measuring the absolute wheal size to measuring the wheal size relative to the negative (diluent) and positive (histamine) controls. A positive SPT simply correlates with the presence of sIgE bound to the surface of cutaneous mast cells. Although the larger the mean wheal diameter provoked, the more likely that a food allergen will be of clinical relevance, the SPT alone is not diagnostic of FA.104-107 When diagnosing OAS, or in cases where SPTs with commercial extracts do not correlate with clinical histories, the SPT technique with fresh or native foods, especially fruits and vegetables, may prove more sensitive.108,109 Negative SPTs occasionally occur in patients with IgE-mediated FA. Therefore, in cases where the history is highly suggestive, further evaluation (for example, physician-supervised oral food challenge) is necessary before telling a patient that he or she is not allergic to a suspected food and may ingest it. 4.2.2.2. Intradermal testsGuideline 5: The EP recommends that intradermal testing should not be used to make a diagnosis of FA. Rationale: Insufficient evidence exists to support the use of intradermal testing for the diagnosis of FA. Moreover, intradermal tests carry a higher risk of adverse reactions than SPTs. Balance of benefits and harms: Although intradermal testing may be more sensitive than skin prick testing for the diagnosis of IgE-mediated FA, there is no evidence to support such claims for protein-induced FA and insufficient evidence to support its routine use in diagnosing carbohydrate-induced FA. In addition, there is a greater risk of systemic adverse allergic reactions from intradermal tests compared with SPTs. Quality of evidence: Low Contribution of expert opinion: Significant Intradermal testing for FA does not provide increased sensitivity in detecting food protein-induced allergic reactions.102 There is suggestive but unconfirmed evidence to support its use in diagnosing a form of carbohydrate-induced IgE-mediated allergy that is a characteristic of some types of red meat allergy.110 4.2.2.3. Total serum IgEGuideline 6: The EP recommends that the routine use of measuring total serum IgE should not be used to make a diagnosis of FA. Rationale: Insufficient evidence exists to support the proposal that measurements of total serum IgE levels can be a sensitive and specific test for FA. Balance of benefits and harms: Although an elevated total serum IgE level is frequently found in atopic individuals and some investigators suggest that it may be useful when interpreting allergen-specific IgE levels, the EP could find no studies to support such a claim. In addition, the sensitivity and specificity of this test compared with the outcome of oral food challenges is insufficient to warrant routine use in evaluating FA. Quality of evidence: Low Contribution of expert opinion: Significant Mehl et al looked at the predictive value of the ratio of sIgE to total IgE for the diagnosis of FA compared with the DBPCFC and concluded that the ratio offered no advantage over sIgE alone in diagnosing FA.111 4.2.2.4. Allergen-specific serum IgEGuideline 7: The EP recommends sIgE tests for identifying foods that potentially provoke IgE-mediated food-induced allergic reactions, but alone these tests are not diagnostic of FA. Rationale: sIgE tests are useful for identifying foods potentially provoking IgE-mediated food-induced allergic reactions, and specified “cutoff” levels, defined as 95% predictive values, may be more predictive than SPTs of clinical reactivity in certain populations, but when used alone they are not diagnostic of FA. Balance of benefits and harms: sIgE tests are very useful for detecting the presence of sIgE antibodies, which indicates the presence of allergic sensitization. Fluorescence-labeled antibody assays have comparable sensitivity to that of SPTs, and the absolute levels of sIgE antibodies may directly correlate with the likelihood of clinical reactivity when compared with oral food challenges for the identification of foods provoking IgE-mediated FA. Quality of evidence: Moderate Contribution of expert opinion: Significant sIgE testing and skin prick testing both depend on the presence of allergen-specific antibodies. Because the former test measures sIgE in the serum and the latter reflects IgE bound to cutaneous mast cells, their results may not always correlate. Serum testing can be especially useful when SPTs cannot be done (for example, due to extensive dermatitis or dermatographism), or when antihistamines cannot be discontinued. sIgE levels were originally measured using the radioallergosorbent test (RAST), but this test has been replaced by more sensitive fluorescence enzyme-labeled assays and the term RAST should be abandoned. It is important to note that results from different laboratories or different assay systems may not be comparable. Wang et al112 examined 50 patients who were between 2 and 20 years of age and used 3 different systems (Phadia ImmunoCAP, Agilent Turbo-MP, and Siemens Immulite 2000) to assess for allergy to milk, egg, and peanut, as well as 3 aeroallergens.112 Each system used slightly different forms of the antigens (for example, skim milk vs freeze-dried milk vs whole milk). Of the 50 patients, 42 had diagnosed FA. Each system provided significantly different measurements of sIgE for the same serum samples. Thus, the predictive values associated with clinical evidence of allergy for ImmunoCAP cannot be applied to other test methods, for example, Turbo-MP and Immunlite. The presence of sIgE reflects allergic sensitization and not necessarily clinical allergy. Several studies comparing the quantity of sIgE to oral food challenges have reported that the greater the levels of sIgE, the higher the probability that ingestion of the food will lead to an allergic reaction. However, the predictive values varied from one study to another.44,51,113-120 This inconsistency may be due to multiple factors, such as patients' ages, duration of food allergen avoidance at the time of testing, selection of patients, and clinical disorders of patients being studied. Undetectable sIgE levels occasionally occur in patients with IgE-mediated FA. Therefore, in cases where the history is highly suggestive, further evaluation (for example, physician-supervised oral food challenge) is necessary before telling a patient that he or she is not allergic to a suspected food and may ingest it. 4.2.2.5. Atopy patch testGuideline 8: The EP suggests that the APT should not be used in the routine evaluation of non-contact FA. Rationale: Insufficient evidence exists to support the use of the APT for the evaluation of FA. Balance of benefits and harms: Although a number of studies have reported that the APT may be useful in the evaluation of FA in patients with AD and EoE, there is no agreement on the appropriate reagents, methods, or interpretation of these tests. When compared with oral food challenges, APTs show highly variable sensitivity and specificity among different studies. Quality of evidence: Low Contribution of expert opinion: Significant In general, a patch test is used to determine allergic sensitivity by applying small pads soaked with allergen to the unbroken skin. The APT is a specific type of patch test.121 The only difference between the APT and other patch tests is the antigen that is being tested. The APT uses allergens (for example, food allergens) that provoke only IgE-mediated reactions, whereas all other patch tests use antigens that typically provoke T cell-mediated reactions. All patch tests are performed the same way. The APT is an investigational tool for diagnosing FA and is generally used to assess delayed, or non-IgE-mediated, reactions to an allergen. However, there are no standard reagents available, and no studies that specifically addressed the methodology of APTs met the criteria to be included in the RAND evidence report. Some studies reported that test material was applied directly to the skin for 48 hours and read at 72 hours following application,122,123 although most studies reported applying foods (fresh or from powders) in aluminum discs to the skin for 48 hours, with a final reading at 72 hours after application. The sensitivity and specificity of the test varied between studies and may have been affected by the presence of AD and the age of the patient. No studies compare the use of different food allergen preparations. Two large studies conclude that there is no significant clinical value in using APTs for diagnosing FA.121,124 4.2.2.6. Use of skin prick tests, sIgE tests, and atopy patch tests in combinationGuideline 9: The EP suggests not using the combination of SPTs, sIgE tests, and APTs for the routine diagnosis of FA. Rationale: No literature supports the proposal that the use of SPTs, sIgE tests, and APTs in combination for the evaluation of FA provides any significant advantage over the use of SPTs or sIgE tests alone. Balance of benefits and harms: Combining the results of SPTs, sIgE tests, and APTs may provide higher positive and negative predictive values than any test alone, but use of all 3 tests is time consuming, inconvenient for the patient, and provides marginally improved positive and negative predictive values that may not be clinically relevant. However, a combination of 2 of these methods is sometimes more helpful for identifying foods likely to induce allergic reactions. Quality of evidence: Low Contribution of expert opinion: Significant A few studies show that various combinations of SPTs, sIgE tests, and APTs improved the sensitivity and specificity over the use of individual tests.121,124,125 However, the small number of studies that calculated the proportion of patients for whom 2 or more tests could obviate the need for a DBPCFC found these proportions to be quite small. 4.2.2.7. Food elimination dietsGuideline 10: The EP suggests that elimination of 1 or a few specific foods from the diet may be useful in the diagnosis of FA, especially in identifying foods responsible for some non-IgE-mediated food-induced allergic disorders, such as FPIES, AP, and Heiner syndrome, and some mixed IgE- and non-IgE-mediated food-induced allergic disorders, such as EoE. Rationale: The use of an elimination diet in combination with a convincing history may be sufficient to diagnose FA in several food-induced allergic disorders, including FPIES, AP, and Heiner syndrome, and some mixed IgE- and non-IgE-mediated food-induced allergic disorders, such as EoE. Balance of benefits and harms: In several non-IgE-mediated FA disorders and EoE, a suggestive medical history plus the elimination of the suspected food resulting in the resolution of symptoms provides evidence for the diagnosis of FA. In these situations, there are no known laboratory tests that are diagnostic of the causative food, and the oral food challenge, while a potentially useful diagnostic test, may provoke significant morbidity. Thus, many health care professionals base the initial diagnosis on history and clearing of symptoms while on the elimination diet, and reserve the oral food challenge for evaluating the eventual resolution of the disorder (ie, development of tolerance). Quality of evidence: Low Contribution of expert opinion: Significant RAND found no studies meeting the inclusion criteria to support the diagnostic value of using dietary elimination trials or of food/symptoms diaries for the diagnosis of FA. However, given the morbidity of oral food challenges in some non-IgE-mediated food-induced allergic disorders, some investigators believe that a convincing history plus clearing of symptoms with the initiation of an elimination diet for a particular food is sufficient to make the diagnosis of FA. However, prolonged elimination diets that omit multiple foods have been reported to induce severe malnutrition;126-128 therefore, confirmatory diagnostic studies must be performed in such cases to confirm the diagnosis of FA. 4.2.2.8. Oral food challengesGuideline 11: The EP recommends using oral food challenges for diagnosing FA. The DBPCFC is the gold standard. However, a single-blind or an open-food challenge may be considered diagnostic under certain circumstances: if either of these challenges elicits no symptoms (ie, the challenge is negative), then FA can be ruled out; but when either challenge elicits objective symptoms (ie, the challenge is positive) and those objective symptoms correlate with medical history and are supported by laboratory tests, then a diagnosis of FA is supported. Rationale: DBPCFC is the most specific test for diagnosing FA. However, due to the expense and inconvenience of DBPCFCs, single-blind and open-food challenges may be used in the clinical setting. Balance of benefits and harms: The DBPCFC markedly reduces potential bias of patients and supervising health care professionals that may interfere with the appropriate interpretation of oral food challenges, and corresponds most closely to the natural ingestion of food. Other diagnostic tests lack specificity and may lead to the unnecessary exclusion of foods from patients' diets. However, the DBPCFC is time consuming, expensive, and, like any form of oral food challenge, subjects the patient to potential severe allergic reactions. Single-blind and open-food challenges are frequently used to screen patients for FA. When negative, they may be considered diagnostic in ruling out FA, and when positive (ie, when “immediate” objective allergic symptoms are elicited), they may be considered diagnostic in patients who have a supportive medical history and laboratory data. Quality of evidence: High Contribution of expert opinion: Moderate Note: Because of the inherent risk, an oral food challenge must be conducted at a medical facility that has onsite medical supervision and appropriate medicines and devices on hand. A positive SPT or sIgE test result is indicative of allergic sensitization, but these findings alone may or may not be clinically relevant. Most investigators in the field agree that verification of clinical reactivity requires well-designed oral food challenge testing.102,103,129-133 Prior to initiating an oral food challenge, suspected foods are eliminated from the diet for 2 to 8 weeks, depending on the type of food-induced allergic reaction being examined (for example, urticaria vs EoE).133,134 All foods in question must be strictly avoided simultaneously. An infant's diet can be limited to a hypoallergenic formula. For exclusively breast-fed infants, either the suspected food is eliminated from the mother's diet or the baby is fed a hypoallergenic formula until the allergic food is identified. After documenting significant improvement on dietary elimination, the challenge test is carried out while the patient is on minimal or no symptomatic medication. The test should be designed and performed under medical supervision to document the dose that provokes the reaction and to administer symptomatic treatment, which may require management of anaphylaxis (section 6), and the medical personnel should have experience in carrying out such challenges. Oral food challenge begins with a low dose (intended to be lower than a dose that can induce a reaction135,136). While monitoring for any allergic symptoms, the dose is gradually increased, until a cumulative dose at least equivalent to a standard portion for age is consumed. The challenge may be carried out in an open fashion in infants, but in older children, single-blind food challenges or DBPCFCs may be necessary to minimize patient and physician bias. Using DBPCFC, several studies have shown that only about one third of the suspected foods are found to be truly allergic.103 In addition to verifying FA, challenge testing prevents unnecessary dietary avoidance and enhances compliance with the elimination diet. Nevertheless, because of the risk of a severe reaction, intentional challenge should be avoided in patients who have recently experienced a life-threatening reaction to a particular food, particularly if it occurred more than once. In the case of post-prandial exercise-induced reactions, food challenge should be followed by exercise.92 There is currently no internationally accepted, standardized protocol for performing and interpreting DBPCFCs, although reviews outlining benefits and deficiencies have been published.133,135-137 4.2.2.9. Nonstandardized and unproven proceduresGuideline 12: The EP recommends not using any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA:
Rationale: There is a lack of evidence demonstrating that any of these nonstandardized tests has any value in the diagnosis of FA. However, although basophil histamine release/activation is not a routine diagnostic test for IgE-mediated FA, it is commonly used as a research tool. Balance of benefits and harms: The utility of these tests has not been validated for the diagnosis of FA and may result in false positive or false negative diagnoses, leading to unnecessary dietary restrictions or delaying the appropriate diagnostic workup, respectively. Quality of evidence: Low Contribution of expert opinion: Significant 4.3. Diagnosis of non-IgE-mediated immunologic adverse reactions to foodThe diagnosis of non-IgE-mediated FA can be challenging. Prior to a diagnostic workup, it may be difficult to distinguish an IgE-mediated allergy from a non-IgE-mediated allergy based on medical history and physical examination alone. Some distinct non-IgE-mediated conditions are associated with FA. T cells have been shown to play a central role in celiac disease. Studies have also shown that T cells may mediate the pathogenesis of some other non-IgE-mediated adverse reactions to food. A number of diagnostic tools have been suggested for use in diagnosing non-IgE-mediated reactions, including DBPCFC, contact dermatitis patch testing, APT, intradermal testing, lymphocyte activation assays, food-specific IgG testing, and endoscopic biopsy. Specific examples of non-IgE-mediated adverse reactions to foods include:
4.3.1. Eosinophilic gastrointestinal diseasesGuideline 13: The EP suggests that SPTs, sIgE tests, and APTs may be considered to help identify foods that are associated with EoE, but these tests alone are not sufficient to make the diagnosis of FA. The role of these tests in the diagnosis of other EGIDs has not been established. Rationale: SPTs, sIgE tests, and APTs alone are insufficient to establish a causal role for FA in EoE, but they may be useful in identifying foods that should be investigated further with other diagnostic tests, such as dietary elimination, oral food challenge, and endoscopy and esophageal biopsy. Balance of benefits and harms: Some studies suggest that SPTs, sIgE tests, and APTs may be of value in identifying foods that cause symptoms of EoE. However, the utility of these tests has not been validated for the diagnosis of FA in EoE or other EGIDs and may result in false positive or false negative diagnoses. Quality of evidence: Low Contribution of expert opinion: Significant EGIDs are a diverse group of intestinal diseases that require endoscopic analysis with mucosal biopsy to make the diagnosis. The diagnosis of EoE, which is a common form of EGID, is defined by an esophageal biopsy with the finding of >15-20 eosinophils per high power field. A method for demonstrating that FA is relevant to the course of EoE is resolution of symptoms and esophageal eosinophilia following dietary elimination, and recurrence of esophageal eosinophilia with reintroduction of the suspected food.17 Because food allergens are thought to play a large role in the pathogenesis of these diseases, sIgE tests and SPTs are used to identify potentially relevant foods and design an optimal elimination diet. However, little evidence supports the use of these tests in predicting the severity of EGID symptoms,147 and no studies have systematically assessed the positive and negative predictive values of SPT or sIgE results in evaluating the potential relevant role of FA in EoE. Results from 1 study suggest some benefit of APT in identifying suspect food allergens,147 but this has not been confirmed in other studies. 4.3.2. Food protein-induced enterocolitis syndromeGuideline 14: The EP recommends using the medical history and oral food challenge to establish a diagnosis of FPIES. However, when history indicates that infants or children have experienced hypotensive episodes or multiple reactions to the same food, a diagnosis may be based on a convincing history and absence of symptoms when the causative food is eliminated from the diet. Rationale: FPIES is diagnosed based on a supportive medical history, resolution of symptoms with the elimination of the causative food, and, in many cases, provocation of symptoms following an open or single-blind oral food challenge. Balance of benefits and harms: There are no laboratory studies with demonstrated specificity and sensitivity to diagnose FPIES, so an oral food challenge is necessary to establish the diagnosis. Although the oral food challenge may induce significant symptoms, there are no alternative methods with adequate predictability to diagnose FPIES. However, when the history is very compelling (for example, 2 or more reactions with classic symptoms to the same food in a 6-month period and elimination of symptoms when the causative food is removed from the diet), an oral food challenge may not be necessary to make the diagnosis. Because this disorder often lasts only a few years, however, subsequent oral food challenge is warranted to determine when FPIES has resolved and the food elimination diet can be terminated. Quality of evidence: High Contribution of expert opinion: Moderate FPIES is a severe systemic response to food protein that typically occurs 1 to 4 hours after the ingestion of the causative food and frequently develops in the first few years of life. FPIES can manifest in young infants who frequently are breast-fed and presents as blood-streaked or hemoccult-positive stools in an infant who otherwise appears healthy. Symptoms include vomiting, diarrhea, acidosis, and in some cases shock.13,148-150 Laboratory studies consistent with this diagnosis include an elevated white blood cell count with a left shift and elevated platelet count. Since FPIES occurs when the infant's diet is quite limited, history is often helpful in identifying food triggers. Because FPIES is a non-IgE-mediated disorder, sIgE tests and SPTs are typically negative. Endoscopy may reveal a mixed eosinophilic and neutrophilic infiltrate but is not required to make the diagnosis. Young infants who develop FPIES in response to one formula or food are at greater risk of developing allergic reactions to other whole-protein formulas. Therefore, hypoallergenic formulas are recommended.148,151 Because hypotension may develop in up to 15% of cases, children should be challenged in a setting where intravenous hydration is readily available.133 4.3.3. Food protein-induced allergic proctocolitisGuideline 15: The EP recommends using the medical history, resolution of symptoms when the causative food is eliminated from the diet, and recurrence of symptoms following an oral food challenge to diagnose AP. Rationale: The evidence supports the conclusion that food protein-induced AP can be diagnosed based on a supportive medical history, resolution of symptoms with the elimination of the causative food, and recurrence of symptoms following an oral food challenge. Balance of benefits and harms: Because there are no laboratory studies with sufficient specificity and sensitivity to diagnose food protein-induced AP, an oral food challenge is necessary to establish the diagnosis. Although the food challenge may induce blood in the stools, symptoms of AP are generally benign, and there are no alternative methods with adequate predictability to diagnose AP. In cases with a classic history of AP, a normal physical examination and resolution of symptoms following elimination of the causative food leads many investigators to believe that an oral food challenge is not required to establish the diagnosis. Since this disorder often lasts only 1 to 2 years, repeated challenges are warranted to determine when food elimination diets can be terminated. Quality of evidence: Moderate Contribution of expert opinion: Significant AP is a common transient disease of infancy, typically resolving in the first 1 to 2 years of life,152 that manifests itself as the passage of mucoid, blood-streaked stools in an otherwise healthy infant. AP also can manifest as chronic emesis, diarrhea, and failure to thrive. Upon re-exposure to the offending food after a period of elimination, a subacute syndrome can present with repetitive emesis and dehydration. Typically AP is associated with the ingestion of cow's milk, soy milk, or human breast milk during infancy. Reports also exist of adults experiencing crampy abdominal pain, severe vomiting, light-headedness, and lethargy 2 to 3 hours following the ingestion of crustacean shellfish.153 Because AP is a non-IgE-mediated FA, sIgE and SPT results are typically negative. Although colonoscopy and biopsy are not generally necessary to make the diagnosis, they will reveal lesions that are confined to the large bowel and consist of mucosal edema with infiltration of eosinophils in the epithelium and lamina propria. In severe lesions with crypt destruction, polymorphonuclear leukocytes are also prominent.154 A recent study found that about one third of suspected infants had no evidence of eosinophils on biopsy, and AP resolved without a change in breast-feeding or formula.155 4.3.4. Food protein-induced enteropathy syndromeFood protein-induced enteropathy syndrome is an uncommon disorder that presents in young infants as chronic diarrhea (steatorrhea in up to 80% of cases), weight loss, and growth failure. Symptoms are similar to those observed in patients with celiac disease, except that they appear in young infants. The disorder is characterized by generalized malabsorption156 (of fat, carbohydrates, and other nutrients), thought to be due to changes in the structure of the intestinal mucosa. It is most often due to milk allergy,157 but also has been reported due to an allergy to soy, chicken, rice, and fish. Moderate anemia, hypoproteinemia, and deficiency of the vitamin K factors may occur. Diagnosis is based on the clinical symptoms, resolution with allergen elimination, and recurrence of symptoms following an oral food challenge. Treatment consists of strict allergen elimination from the diet. Virtually all affected patients “outgrow” their symptoms by 2 to 3 years of age, and therefore follow-up oral food challenges are recommended to determine when allergen elimination diets can be terminated. 4.3.5. Allergic contact dermatitisGuideline 16: The EP recommends using the medical history, including the absence of symptoms while the causative food is avoided, and positive patch tests to diagnose ACD. Rationale: There are a limited number of well-controlled studies demonstrating the utility of these methods in diagnosing ACD. However, the concept that patch testing can be useful in establishing the diagnosis of ACD is based on both the underlying immunologic mechanism involved in the disease and observations from general medical practice. Balance of benefits and harms: Traditionally, patch testing has been used to support history in diagnosing ACD. Although there are insufficient well-controlled studies to demonstrate the benefits of these methods in diagnosing ACD, the concept of patch testing largely fits with the immunopathogenic mechanism involved. The harm of avoiding contact with the food identified by this method appears minimal. Quality of evidence: Moderate Contribution of expert opinion: Significant ACD is a cell-mediated allergic reaction and may be triggered by foods or contaminants in foods. The immediate reactions in ACD may be initiated by contact with chemical moieties in the food, such as oleoresins in fruits and vegetables or spices. Examples include garlic causing contact dermatitis of the hands, mango causing perioral dermatitis, or raw chestnut causing hand and perianal dermatitis.27 A detailed medical history will aid in the diagnosis of ACD. Patch testing may be performed with standardized contact allergens or suspected allergens (ie, food allergens) applied to a healthy area of the skin, with eczematous reactions assessed 48 to 72 hours later.28 Positive reactions must be distinguished from simple irritant reactions. Furthermore, positive tests are a sign of sensitization to the allergen, but the clinical relevance of such sensitization needs to be assessed in the context of other clinical signs. 4.3.6. Systemic contact dermatitisGuideline 17: The EP suggests using the medical history, including the resolution of symptoms while the causative food is avoided, and positive patch tests to establish the diagnosis of systemic contact dermatitis. Rationale: Insufficient well-controlled studies exist to demonstrate the utility of these methods in diagnosing systemic contact dermatitis. Balance of benefits and harms: Traditionally, patch testing has been used to support a suggestive history in diagnosing this rare condition. Although there are few well-controlled studies to demonstrate the benefits of these methods in diagnosing systemic contact dermatitis, those that exist support the utility of these methods. The harm of eliminating a small number of foods on this basis appears minimal. Quality of evidence: Low Contribution of expert opinion: Significant Systemic contact dermatitis158 is a rare disorder consisting of generalized eczematous dermatitis associated with systemic symptoms such as fever, headache, rhinitis, and GI complaints that develop after oral or parenteral exposure to an allergen, to which the individual has been sensitized through the skin. Metals and fragrances are allergens that play an important role in food-associated systemic contact dermatitis. Metals found in foods159 and associated with systemic contact dermatitis include nickel, cobalt, and chromium. Balsam of Peru, a fragrance associated with systemic contact dermatitis, consists of several chemicals, including cinnamic acid, cinnamaldehyde, cinnamic alcohol, vanillin, eugenol, methyl cinnamate, and benzyl cinnamate. This fragrance may be present in alcohol, chocolate, citrus fruits, pickled vegetable, spices, and tomatoes.27 Patch testing with standardized contact allergens or suspected allergens may assess contact allergen sensitization, but sIgE testing is usually negative. Clinical relevance of positive patch testing requires assessment of the clinical context and may require food elimination or food challenges. 4.4. Diagnosis of IgE-mediated contact urticariaGuideline 18: The EP suggests using the medical history, including the absence of symptoms while the causative food is avoided, positive sIgE tests or SPTs, and positive immediate epicutaneous skin tests (for example, positive immediate responses to APTs), to establish the diagnosis of food-induced IgE-mediated contact urticaria. Rationale: There are a limited number of well-controlled studies demonstrating the utility of these methods in diagnosing IgE-mediated contact urticaria, but traditionally these methods have been used and found to correlate with clinical symptoms. Balance of benefits and harms: Although there are few well-controlled studies to demonstrate the benefits of these methods in diagnosing IgE-mediated contact urticaria, test results appear to correlate with clinical symptoms. The potential harm of avoiding contact with foods provoking contact urticaria appears to be minimal. Quality of evidence: Low Contribution of expert opinion: Significant Contact urticaria can be of 2 types, either IgE mediated or non-IgE mediated.160 In IgE-mediated contact urticaria, substances present in foods interact with sIgE bound to cutaneous mast cells, leading to the release of histamine and other inflammatory mediators. Localized or generalized urticaria, as well as systemic symptoms, may result. sIgE-mediated contact urticaria may be assessed with APTs, SPTs, or sIgE tests, although there is no standardization of diagnostic methodology. In non-IgE-mediated contact urticaria, systemic symptoms are rarely seen. 4.5. Knowledge gapsAt the current time, the oral food challenge is the gold standard for diagnosing FA. This test is accurate and sensitive, but also presents the greatest risk to the patient. Other laboratory tests used to diagnose FA, although safer for the patient, all have significant drawbacks, for example:
The lack of objective data available to adequately evaluate existing tests to diagnose FA is reflected in the fact that of 18 guidelines proposed in this section, 15 are heavily dependent on expert opinion and only 3 are based on evidence of “high quality.” In conclusion, studies to identify sensitive and specific biomarkers that correlate with clinical reactivity to both IgE- and non-IgE-mediated food-induced allergic reactions and clinical FA are needed for the development of newer and safer laboratory tests. 5. Management of Nonacute Allergic Reactions and Prevention of Food AllergyThis section of the Guidelines addresses the management and prevention of nonacute and nonsevere allergic reactions to food in individuals diagnosed with FA. Management and prevention of individuals at risk for developing FA and specific concerns about vaccination in individuals with egg allergy also are addressed. 5.1. Management of individuals with food allergy5.1.1. Dietary avoidance of specific allergens in IgE-mediated food allergyGuideline 19: The EP recommends that individuals with documented IgE-mediated FA should avoid ingesting their specific allergen or allergens. Rationale: The EP recognizes that allergen avoidance is a strategy that is unproven in RCTs. However, allergen avoidance is currently the safest strategy for managing FA. Balance of benefits and harms: For individuals with FA, ingesting food allergens can cause allergic reactions ranging in severity from mild to life-threatening. Carefully planned allergen-free diets can provide sufficient nutrients to maintain a healthy and active life. In addition, there is no evidence that strict food avoidance (compared with less strict avoidance) has any effect on the rate of natural remission to a specific food allergen. Quality of evidence: Low Contribution of expert opinion: Significant Individuals with documented IgE-mediated FA should avoid ingesting their specific allergen or allergens. However, health care professionals should work with their patients to decide whether certain cross-reactive foods also should be avoided. For patients with a known allergy to a food, the rate of clinically relevant cross-reactivity to related foods varies, as indicated in Appendix D Table S-I, which shows data based on limited studies. Therefore, the health care professional may need to individualize additional testing and patient instructions depending on the foods involved in these situations, taking into consideration that:
5.1.2. Dietary avoidance of specific allergens in non-IgE-mediated food allergyGuideline 20: The EP recommends that individuals with documented non-IgE-mediated FA should avoid ingesting their specific allergen or allergens. Rationale: The literature cannot readily be divided on the basis of IgE-mediated and non-IgE-mediated reactions. In general, the management of non-IgE-mediated FA is similar to that of IgE-mediated FA, in that the medical history, the age of the individual, and the specific food allergen are all-important considerations in developing the management plan. Although there are relatively few high-quality studies regarding treatment for non-IgE-mediated FA, the bulk of the evidence suggests that food avoidance is the best management plan. Balance of benefits and harms: For individuals with FA, ingesting trigger foods can cause allergic reactions and serious illness. Carefully planned allergen-free diets can provide sufficient nutrients to maintain a healthy and active life. In addition, there is no evidence that strict food avoidance (compared with less strict avoidance) has any effect on the rate of natural remission to a specific food allergen. Quality of evidence: Low Contribution of expert opinion: Significant 5.1.3. Effects of dietary avoidance on associated and comorbid conditions, such as atopic dermatitis, asthma, and eosinophilic esophagitisGuideline 21: In individuals with documented or proven FA who also have 1 or more of the following―AD, asthma, or EoE―the EP recommends avoidance of their specific allergen or allergens. Rationale: Only limited study data exist on this issue. In appropriately diagnosed individuals with FA, food allergen avoidance may reduce the severity of AD or EoE. Current evidence is not available to indicate whether food allergen avoidance will alter the course of AD, asthma, or EoE. Balance of benefits and harms: This approach is not an additional burden for individuals already practicing food avoidance to manage FA. Quality of evidence: Low Contribution of expert opinion: Significant In a nonrandomized comparative study, Agata et al75 concluded that an elimination diet was a good treatment for AD associated with FA and that sIgEs to food antigens were useful as indices of the effect of elimination diets. However, it is important to note that the study was conducted in a small number of patients and the evidence quality is considered low. Guideline 22: In individuals without documented or proven FA, the EP does not recommend avoiding potentially allergenic foods as a means of managing AD, asthma, or EoE. Rationale: No conclusive evidence exists to suggest that avoiding food allergens reduces the severity of AD, asthma, or EoE in individuals who are not sensitized and have not demonstrated specific clinical reactivity to foods. Balance of benefits and harms: Unnecessary food avoidance could place individuals at risk for nutritional deficiencies and growth deficits. There is no known benefit to avoiding potentially allergenic foods (such as (cow's) milk, egg, peanut, tree nuts, wheat, soy, fish, and crustacean shellfish). Quality of evidence: Moderate Contribution of expert opinion: Moderate The EP identified 2 systematic, high-quality reviews that evaluated the effect of dietary exclusion for treating AD.
Similarly, the EP found no high-quality studies specifically addressing food allergen avoidance in which the patients did not have documented or proven FA but did have other comorbid conditions, such as asthma or EoE. 5.1.4. Food avoidance and nutritional statusGuideline 23: The EP recommends nutritional counseling and regular growth monitoring for all children with FA. Rationale: Although few studies have evaluated whether food allergen avoidance results in nutritional deficiency, the EP acknowledges that obtaining adequate nutrition is a concern in this population. Balance of benefits and harms: Avoidance of specific allergens can limit the availability of nutritious food choices. Nutrition counseling can help patients plan and consume an allergen-free yet nutritionally adequate diet. Quality of evidence: Low Contribution of expert opinion: Significant No randomized clinical studies have been undertaken to address whether food allergen avoidance diminishes nutritional status. However, studies166,167 in which growth measurements were evaluated against diet records suggest that children with FA are at risk for inadequate nutritional intake. Christie et al166 estimated energy and nutrient intakes based on 3-day diet records. The age-matched, consecutive sampling, cross-sectional study had 98 children with FA and 99 without. The study found that:
Tiainen et al167 collected 6-day diet records for 18 children with milk allergy and 20 healthy children, and found that:
5.1.5. Food labeling in food allergy managementGuideline 24: The EP suggests that individuals with FA and their caregivers receive education and training on how to interpret ingredient lists on food labels and how to recognize labeling of the food allergens used as ingredients in foods. The EP also suggests that products with precautionary labeling, such as “this product may contain trace amounts of allergen,” be avoided. Rationale: Although current requirements under the Food Allergen Labeling and Consumer Protection Act (FALCPA) require food labels to disclose the presence of any of the 8 major food allergens when used as ingredients, the law does not address precautionary labeling. Precautionary labeling is voluntary and is used at the manufacturer's discretion. Ingredient labeling is not completely effective in preventing unintentional exposure to allergens. Balance of benefits and harms: Ingredient lists on food packages can help consumers identify the contents of products, but may be difficult to interpret. FALCPA provides for the use of plain-language labels for ingredients that are, or that contain, major food allergens. Difficult-to-interpret voluntary precautionary labeling statements place individuals at risk for unintentional exposure to allergens. Quality of evidence: Low Contribution of expert opinion: Significant FALCPA, which was passed by the US Congress in 2004, identified 8 major food allergens (milk, egg, peanut, tree nuts, soy, wheat, fish, and crustacean shellfish) that are responsible for 90% or more of serious adverse food-induced reactions in the United States. Under FALCPA, products containing these major food allergens must clearly list the food allergen on the label in simple language. The 1 exemption is for highly refined oils and their derivatives that are produced from these major foods. However, less well-refined and cold-pressed oils can contain protein and can be hazardous for individuals with FA.168 FALCPA does not currently regulate voluntary disclaimers such as “this product does not contain peanuts, but was prepared in a facility that makes products containing peanuts” or “this product may contain trace amounts of peanut.” Such disclaimers can leave consumers without adequate knowledge to make objective decisions. The EP identified 10 studies that examined whether standards for precautionary food labeling are effective in preventing food-induced allergic reactions. No study explicitly attempted to infer a cause-and-effect relationship between changes in frequency of severe symptoms from unintentional exposure (for example, to peanut) as a consequence of implementing food labeling. The identified studies mostly assessed knowledge and preferences for food labeling. Two studies undertaken prior to FALCPA, and 1 published after FALCPA, were particularly helpful in evaluating food labels.
Similar problems in identification were reported in a study of parents of children with milk allergy in Brazil,172 and difficulties interpreting labels and general dissatisfaction with current labels were noted in studies from the United States, the United Kingdom, the Netherlands, and Greece.173-175 With global variations in culinary practices, labeling laws vary among geographic regions. In the European Union, for example, celery, mustard, sesame, lupine, and molluscan shellfish have been identified as major allergens. In Japan, buckwheat is a major allergen. The globalization of the food supply and exposure of Americans to new foods or culinary practices may lead to increases in the number of major food allergens in the United States. 5.1.6. When to re-evaluate patients with food allergyGuideline 25: The EP suggests follow-up testing for individuals with FA depending on the specific food to which the individual is allergic. Whether testing is done annually or at other intervals depends on the food in question, the age of the child, and the intervening medical history. Rationale: Insufficient evidence exists to make a specific recommendation as to the timing for re-evaluating individuals for FA. Balance of benefits and harms: It is recognized that children will likely outgrow allergies to certain foods, such as milk, egg, soy, and wheat, and be less likely to outgrow allergies to other foods, such as peanut, tree nuts, fish, and crustacean shellfish. Results of follow-up testing can guide decision making regarding whether and when it is safe to introduce or re-introduce allergenic food into the diet. Quality of evidence: Moderate Contribution of expert opinion: Significant Insufficient evidence exists for the EP to recommend a specific optimal interval for FA follow-up testing for each food. It is known that allergy to some foods (such as milk and egg) is outgrown quickly, whereas allergy to other foods (such as peanut and tree nuts) is not. If the patient has had a recent FA reaction, then there is little reason to retest for several years. Annual testing is often the practice for determining whether allergy to milk, egg, soy, and wheat have been outgrown, and the testing interval is extended to 2 to 3 years for allergy to peanut, tree nuts, fish, and crustacean shellfish. However, the EP noted that these testing schedules are not supported by objective evidence.45,52,176 5.1.7. Pharmacologic intervention for the prevention of food-induced allergic reactions5.1.7.1. IgE-mediated reactionsGuideline 26: There are no medications currently recommended by the EP to prevent IgE-mediated food-induced allergic reactions from occurring in an individual with existing FA. Rationale: The current evidence does not support the use of pharmacologic therapy for IgE-mediated reactions to food. Balance of benefits and harms: Pharmacologic agents have the potential to prevent or lessen the severity of food-induced allergic reactions by altering the immune response, but these agents may display significant side effects and predispose individuals to an increased risk for infection. Only limited safety and cost-effectiveness data are currently available. Quality of evidence: Moderate Contribution of expert opinion: Significant 5.1.7.2. Non-IgE-mediated reactionsGuideline 27: There are no medications currently recommended by the EP to prevent non-IgE-mediated food-induced allergic reactions from occurring in an individual with existing FA. Rationale: The current evidence does not support the use of pharmacologic therapy to prevent non-IgE-mediated FA reactions. Balance of benefits and harms: The use of swallowed corticosteroids has the potential to lessen the severity of or prevent future food-induced allergic reactions, but these medications may cause significant side effects and predispose individuals to an increased risk for infection. Nevertheless, swallowed corticosteroids have been shown to be beneficial in the treatment of EoE.177,178 Quality of evidence: Moderate Contribution of expert opinion: Significant 5.1.8. Pharmacologic intervention for the treatment of food-induced allergic reactionsAllergen avoidance is the first line of treatment for FA, and use of antihistamines, as needed, remains the mainstay of managing (as opposed to preventing) symptoms of nonsevere food-induced allergic reactions. However, drug therapy has been used to treat FA in cases where allergen avoidance is extremely difficult or results in nutritional deficiencies. Drugs that alter the immune response to the allergen are commonly considered the most likely candidates for such therapy in the future, but these treatments are not currently recommended (see Guideline 28). The EP identified several RCTs that have evaluated immune-altering drugs to treat FA.178-182 These RCTs studied the effect of:
Although astemizole and anti-IgE therapy showed positive results (cromolyn results were negative), these studies provide support for the value of antihistamine therapy and the continued evaluation of anti-IgE therapy for the treatment of FA. 5.1.9. Immunotherapy for food allergy management5.1.9.1. Allergen-specific immunotherapyGuideline 28: The EP does not recommend using allergen-specific immunotherapy to treat IgE-mediated FA. Rationale: Allergen-specific immunotherapy improves clinical symptoms of FA while on treatment. However, it is currently difficult to draw conclusions on the safety of such an approach and whether clinical tolerance (ie, improvement in clinical symptoms that persists even after allergen-specific immunotherapy is discontinued) will develop with long-term treatment. Balance of benefits and harms: Allergen-specific immunotherapy can improve clinical symptoms of FA for some patients. However, additional safety and efficacy data are needed before such treatment can be recommended. Because of the risk of severe reactions, the approach should only be used in highly controlled settings. Quality of evidence: Low Contribution of expert opinion: Significant Immunotherapy, which alters the immune response to allergens as a means to treat FA, can be accomplished by using small amounts of the allergic food (allergen-specific immunotherapy) or cross-reactive allergens (specific immunotherapy with cross-reactive allergens) to desensitize the patient. Immunotherapy is a promising approach for achieving desensitization and perhaps even long-term tolerance. Achieving either of these outcomes is likely to depend, in part, on:
In several research clinical trials, oral and sublingual immunotherapy for FA have been found to be generally well-tolerated and safe in highly controlled clinical settings.183-189 However, few studies have provided extensive safety data, and systemic reactions can occur at previously tolerated doses of allergen, especially after exercise or viral illness.190 5.1.9.2. Immunotherapy with cross-reactive allergensGuideline 29: The EP does not recommend immunotherapy with cross-reactive allergens for treating IgE-mediated FA. Rationale: Although some evidence exists to suggest that specific immunotherapy with cross-reactive allergens is beneficial in treating FA, additional safety and efficacy data are needed before such treatment can be recommended. Balance of benefits and harms: It has been hypothesized that immunotherapy with cross-reactive antigens could benefit patients with FA, yet the safety of this approach has been evaluated in a highly controlled setting in only 1 study to date.191 Replication of these findings with additional safety and efficacy data in clinical practice settings is needed. Quality of evidence: Low Contribution of expert opinion: Significant Food allergen cross-reactivity was previously defined in section 2.1.1. 5.1.10. Quality-of-life issues associated with food allergyGuideline 30: The EP recommends that patients with FA and their caregivers be provided with information on food allergen avoidance and emergency management that is age and culturally appropriate. Rationale: Food-allergen avoidance and the risk of severe allergic reactions can have substantial daily consequences for patients and their caregivers. Balance of benefits and harms: Patients with FA and their caregivers (especially mothers) can experience anxiety and diminished quality of life because of the risk of anaphylaxis and the burden of selecting or preparing allergen-free foods. Concerns may change as patients with FA mature. Knowledge and skills related to management of FA may improve patient and caregiver self-efficacy, quality of life, and successful allergen avoidance. Quality of evidence: Low Contribution of expert opinion: Significant 5.1.10.1. Effects of food allergy on anxiety and quality of lifeThere is a moderate amount of evidence on the disruptive impact of FA on patient anxiety and quality of life, yet only limited information exists on successful therapeutic strategies by caregivers. A survey by King et al192 of 46 families who had a child with peanut allergy asked members of the family to complete quality of life, anxiety, and perceived stress scales. The survey found that:
Another survey, by Ostblom et al,193 compared 212 children who were 9 years old with FA with 221 children with allergic diseases and no FA. The survey found that:
As children transition into adolescence and adulthood, they have increased responsibility regarding food selection. Their vigilance in avoiding allergens may depend in part on whether they remember experiencing anaphylaxis. One study found that young adults with FA, who were aged 18 to 22 years and reported having experienced an anaphylactic reaction, described their disease as more severe, reported more worry about their disease, and rated their parents as more overprotective than young adults without FA who reported never having experienced anaphylaxis.194 In contrast, 7 teenagers interviewed when they were 13 to 16 year old and who had a history of clinically diagnosed anaphylaxis reported perceiving anaphylaxis as “no big deal.”195 However, most of the teens did not remember experiencing anaphylaxis. Interviewed parents reported anxiety about “handing over” responsibility for avoidance and emergency management to their children. 5.1.10.2. Effects of food allergy on family activitiesBollinger et al196 asked caregivers of children with FA to complete a questionnaire that evaluated their perception of the impact of their child's FA on family activities. Among the 87 families who completed the study:
5.1.11. Vaccinations in patients with egg allergyIn summary: Patients who have generated IgE antibodies to an allergen are at risk for anaphylaxis with systemic exposure to that allergen. Thus, patients who have IgE-mediated egg allergy are at risk for anaphylaxis if injected with vaccines containing egg protein. More detailed information on specific egg-containing vaccines (MMR, MMRV, influenza, yellow fever, and rabies) is provided in sections 5.1.11.1 to 5.1.11.4. Several vaccines are grown in chick embryos or embryonic tissues and always contain egg protein, although the concentration varies widely. Recommendations from the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) Red Book and vaccine manufacturer's package inserts (PIs) for administering such vaccines to patients with egg allergy (summarized in Table V) vary on the basis of the concentration of egg protein in the vaccine and patient history of reactions. Table V2010 ACIP and AAP Red Book recommendations and PI information for administering vaccines to patients with egg allergy
The EP recognizes that changes in these recommendations may occur in the future as there is an increased understanding of the risk factors for allergic reactions and as vaccine manufacturing processes improve and decrease the final egg protein content of vaccines. For the most current recommendations, health care professionals should refer to the AAP and ACIP Web sites: Although ovalbumin is only 1 of the egg proteins in vaccines grown in chick embryos or embryonic tissues, the ovalbumin concentration is often used as a surrogate for the total egg protein concentration. The risk of an egg-allergic reaction to the vaccine appears to correlate with increasing ovalbumin concentration. Therefore manufacturers often, but not always, report the ovalbumin concentration or concentration range in final vaccine lots. Health care professionals should consider this information when evaluating the benefits and risks of the vaccine for a patient with egg allergy. It should be noted that the actual ovalbumin content is often much lower than reported207 and careful testing may permit the eventual safe and efficacious use of the vaccine. Among vaccines potentially contaminated with egg proteins, MMR, MMRV, and Imovax (rabies vaccine) are the only currently available vaccines that may be given without concern in patients with egg allergy because the ovalbumin concentrations are known to be very low. For vaccines with higher concentrations of ovalbumin, their administration to patients with egg allergy presents risk. Published studies describe approaches to reduce the risk, including choosing vaccines with the lowest possible concentrations of ovalbumin and using 2-dose or multiple-dose protocols for administering the vaccine. Although the EP is not able to recommend these approaches at this time, they are briefly described, in the context of influenza vaccine, in section 5.1.11.2. In conclusion, the EP believes that insufficient evidence exists to make broad recommendations concerning the use of all of the vaccines containing egg protein. Moreover, based on their expert opinion and recently published data, the EP suggests that the current ACIP and AAP Red Book recommendations and PI information may be too conservative. 5.1.11.1. Measles, mumps, rubella, and varicella vaccineGuideline 31: The EP recognizes the varying consensus recommendations of the different organizations on this particular vaccine and recommends that children with egg allergy, even those with a history of severe reactions, receive vaccines for measles, mumps, and rubella (MMR) and for MMR with varicella (MMRV). The safety of this practice has been recognized by ACIP and AAP and is noted in the approved product prescribing information for these vaccines.198,199,208 Rationale: MMR and MMRV vaccines are safe for children with egg allergy, even for those with a history of severe reactions. Balance of benefits and harms: Vaccinations can prevent severe disease, and in most states proof of MMR vaccination is required for school entry. Varicella vaccine also is required in most states. The measles component of the vaccine is produced in chicken-embryo fibroblasts, which may be of concern to parents of children with egg allergy. However, MMR and MMRV vaccines are safe to administer to these children because the egg protein content of these vaccines is very low. Severe allergic adverse events attributable to varicella vaccination are extremely rare, and serious allergic reactions could be due to non-egg vaccine components, including gelatin. Quality of evidence: Moderate Contribution of expert opinion: Significant Although the measles component of the MMR vaccine is produced in chicken-embryo fibroblast culture, the vaccine is safe for children with egg allergy, even those with a history of anaphylaxis.209 The monovalent varicella vaccine does not contain egg protein. Therefore, children with egg allergy may be given MMR or the quadrivalent MMRV vaccine without previous skin prick testing.210 Many reactions to the MMR and other vaccines originally attributed to egg have been shown to be due to gelatin in the vaccine.209 5.1.11.2. Influenza vaccineIn summary: The EP concludes that insufficient evidence exists to recommend administering influenza vaccine, either inactivated or live-attenuated, to patients with a history of severe reactions to egg proteins. Severe reactions include a history of hives, angioedema, allergic asthma, or systemic anaphylaxis to egg proteins (or chicken proteins). Less severe or local manifestations of allergy to egg or feathers are not contraindications. However, the EP notes that egg allergy is relatively common among the very patients who would highly benefit from influenza vaccination. Such patients include children and young adults (from 6 months to 18 years old for seasonal influenza, and from 6 months to 24 years old for H1N1 influenza) and all patients with asthma. It should be noted that live-attenuated vaccine is not licensed for use in patients with asthma.211 Although ACIP and AAP, and also the vaccine manufacturers, do not recommend influenza vaccination in patients who are allergic to egg (see Table V), several publications have described different approaches to giving the influenza vaccine to patients with severe allergic reactions to egg. These approaches, which depend on the ovalbumin content and the results of SPTs or intradermal tests with the vaccine, include a single dose of vaccine, 2 doses of vaccine, or multiple doses. However, the evidence supporting these approaches is limited by the small numbers of patients included in each study. Moreover, data indicate that, although the vaccines are relatively safe, there remains some, albeit low, risk of systemic reactions. Also, negative SPT results do not accurately predict safety of vaccination, in that 5% of patients with negative SPTs had systemic reactions to vaccination.212 Briefly:
A 2010 editorial by Kelso217 strongly argues that patients with egg allergy for whom influenza vaccine is indicated can and should be vaccinated to decrease the morbidity and mortality associated with the disease. The author suggests that based on available data, consideration should be given to administering an influenza vaccine with a stated ovalbumin content of less than 1 μg per 0.5 mL dose as a single dose without prior vaccine skin testing. Such immunization would have to take place in a setting where personnel and equipment are available to recognize and treat anaphylaxis. Certainly, the author continues, future studies are needed to validate this approach. However, the editorial concludes with an “editorial opinion” stating that if a low-ovalbumin vaccine is not available, or in the case of more severe egg allergy, a more conservative approach might be warranted. 5.1.11.3. Yellow fever vaccineIn summary: The EP recognizes the current guidelines from the different organizations and recommends against administering yellow fever vaccine to patients with a history of hives, angioedema, allergic asthma, or systemic anaphylaxis to egg proteins, unless an allergy evaluation and testing with the vaccine is done first. This approach has been recognized by ACIP and AAP and is noted in the approved product prescribing information for this vaccine.204,205 Although yellow fever vaccines may contain egg protein, no data are available on whether the concentrations of ovalbumin in these vaccines are low enough to administer without allergy evaluation and testing. Allergy evaluation and testing can provide insight into the potential for risk to an individual. 5.1.11.4. Rabies vaccinesIn summary: The EP recognizes the current guidelines from the different organizations and recommends against administering rabies vaccines to patients with a history of hives, angioedema, allergic asthma, or systemic anaphylaxis to egg proteins, unless an allergy evaluation and testing with the vaccine is done first. This approach has been recognized by ACIP and AAP and is noted in the approved product prescribing information for these vaccines.204,205 One rabies vaccine (Imovax) is not made in chick embryos and does not contain egg protein. This vaccine is not contraindicated in egg-allergic individuals. All other rabies vaccines may contain egg protein but no data are available on whether the concentrations of ovalbumin in these vaccines are low enough to administer without allergy evaluation and testing. 5.2. Management of individuals at risk for food allergy5.2.1. Nonfood allergen avoidance in at-risk patientsGuideline 32: The EP suggests that patients at risk for developing FA do not limit exposure to potential nonfood allergens (for example, dust mites, pollen, or pet dander). Patients at risk for developing FA are defined as those with a biological parent or sibling with existing, or history of, allergic rhinitis, asthma, AD, or FA. This definition of “at risk” is used throughout sections 5.2 and 5.3. Rationale: Insufficient evidence exists to suggest that avoidance of allergens that are not food allergens has any effect on the natural history of FA. Balance of benefits and harms: It has been hypothesized that exposure to nonfood allergens could increase the likelihood of developing an FA in patients at risk for atopic disease, but there are insufficient data to support this hypothesis. Quality of evidence: Low Contribution of expert opinion: Significant It should be noted that the definition of “at risk”218-220 used above differs from the definition of “high risk” used below in section 5.2.3. 5.2.2. Dietary avoidance of foods with cross-reactivities in at-risk patientsGuideline 33: The EP suggests that patients at risk for developing FA do not need to limit exposure to foods that may be cross-reactive with the 8 major food allergens in the United States (milk, egg, peanut, tree nuts, soy, wheat, fish, and crustacean shellfish). Rationale: Insufficient evidence exists to determine whether eating foods that cross-react with the major allergenic foods will cause symptoms. Balance of benefits and harms: It has been hypothesized that exposure to possible cross-reactive foods could result in an allergic response. However, unnecessary food avoidance can result in inadequate nutrient intake and growth deficits. Quality of evidence: Low Contribution of expert opinion: Significant This guideline addresses the question of whether an individual at risk for developing FA (but without a documented allergy to food) should avoid cross-reactive foods that could induce either sensitization or allergy to another food in that food family. For example, should a person be told to avoid eating any legume because it could induce sensitization or allergy to peanut? Because allergenic food proteins may share structural or sequence similarity with other allergenic substances, sensitization to a particular food or even an aeroallergen can result in allergic responses to other foods containing homologous proteins. Despite this theoretical justification for limiting exposure to cross-reactive foods, insufficient evidence exists to evaluate the individual for allergenic cross-reactivity or to limit eating of cross-reactive foods. In addition, there is the potential for inadequate nutrition and growth if otherwise healthful foods are not eaten. 5.2.3. Testing of allergenic foods in patients at high risk prior to introductionIn summary: The EP concludes that insufficient evidence exists to recommend routine FA testing prior to the introduction of highly allergenic foods (such as milk, egg, and peanut) in children who are at high risk of reacting to the introduction of such foods. The definition of children at high risk, in this specific situation, is children with pre-existing severe allergic disease and/or a family history of FA. Nevertheless, there may be some value in FA evaluations that include an oral food challenge for a select group of patients with certain risk factors, such as having a sibling with peanut allergy221 or evidence of another underlying FA (for example, testing for tree nut allergy in a child with peanut allergy). It is possible that an FA evaluation prior to introduction of a food could potentially prevent allergic reactions. However, widespread SPTs and sIgE tests are not recommended because of their poor predictive value. These tests would lead to many clinically irrelevant results and unnecessary dietary restrictions, especially if unconfirmed by oral food challenges. Overall, the risk-to-benefit ratio of FA evaluation should be considered on an individual basis, especially for the highly allergenic foods in high-risk young children. Guideline 34: The EP suggests that the general population of children not be tested for FA to highly allergenic foods prior to their introduction into the diet. The general population of children does not have pre-existing severe allergic disease and also does not have a family history of FA. Rationale: Insufficient evidence exists to suggest whether, or which, foods should be tested prior to introduction. Balance of benefits and harms: Testing prior to introduction could potentially prevent allergic reactions, but there is currently no practical consensus on which (if any) foods should be tested. Quality of evidence: Low Contribution of expert opinion: Significant 5.2.4. Testing in infants and children with persistent atopic dermatitisGuideline 35: The EP suggests that children less than 5 years old with moderate to severe AD be considered for FA evaluation for milk, egg, peanut, wheat, and soy, if at least 1 of the following conditions is met:
Rationale: Insufficient evidence exists to determine the appropriate age to test for response to foods known to commonly cause IgE-mediated FA in infants or young children with AD or other risk factors. In spite of the lack of evidence, the opinion of the EP is that if a child is less than 5 years old and has persistent AD, there is benefit to finding out whether the child is allergic to a food. Balance of benefits and harms: Early diagnosis can lead to better management of FA and reduce the risk of exposure to food antigens. However, testing is time-consuming and costly for patients and their families. In addition, severely restrictive diets may be harmful. Care should be taken to ensure these children are clinically allergic to a food prior to removing it completely from their diet. Quality of evidence: Low Contribution of expert opinion: Significant The question of when to evaluate a child who is less than 5 years old and has moderate to severe AD for FA has been somewhat controversial in the past 20 years. The EP identified the group of children thought to be most at risk for having FA and described them in Guideline 32 (section 5.2.1). It should be noted that milk, egg, and peanut are most often found to be allergenic in this population. Many of these children also have sIgE to wheat and soy. The question of what to recommend for children with delayed food-induced reactions also was considered by the EP. Although a history of a possible delayed reaction to a food is clinically important, it is not diagnostic of FA, and a proper evaluation (medical history and diagnostic testing) should be completed. 5.3. Prevention of food allergy5.3.1. Maternal diet during pregnancy and lactationGuideline 36: The EP does not recommend restricting maternal diet during pregnancy or lactation as a strategy for preventing the development or clinical course of FA. Rationale: Insufficient evidence exists that maternal diet during pregnancy or lactation affects the development or clinical course of FA. Balance of benefits and harms: Restricting exposure to food antigens either during pregnancy or through breast milk has been hypothesized as a means of preventing the development of FA, but it has not been shown conclusively to prevent FA. Adequate nutritional status during pregnancy and lactation is essential for optimal infant health, growth, and development. Quality of evidence: Low Contribution of expert opinion: Significant Several authors have observed that maternal dietary antigens can pass into breast milk and have hypothesized a protective effect of a diet in which certain common allergens are reduced or avoided during pregnancy and lactation by women at risk of having infants likely to go on to develop atopic disease. However, the results of several studies are conflicting, as follows:
5.3.2. Breast-feedingGuideline 37: The EP recommends that all infants be exclusively breast-fed until 4 to 6 months of age, unless breast-feeding is contraindicated for medical reasons. Rationale: There is not strong evidence that breast-feeding has a protective role in preventing atopic disease. However, because of other benefits of breast-feeding, it is recommended that all infants, including those with a family history of atopic disease, be exclusively breast-fed until 4 to 6 months of age, unless breast-feeding is contraindicated for medical reasons. Balance of benefits and harms: Whether exclusive breast-feeding has a beneficial role in preventing atopic disease is unclear, but there are no potential harms associated with exclusive breast-feeding until 4 to 6 months of age. Quality of evidence: Low Contribution of expert opinion: Significant The protective role of breast-feeding (compared with formula feeding) in preventing atopic disease is uncertain, with some studies reporting favorable outcomes associated with breastfeeding224,225 and others reporting no effects.226,227 One RCT showed that early exposure to infant formula instead of breast milk increased the risk of a wide range of allergic reactions, especially AD, in neonates with a family history of atopy.228 The effectiveness of combining exclusive breast-feeding with other interventions, such as dietary avoidance of potential allergenic foods by the mother, to prevent atopic disease is also unclear. In the German Nutritional Intervention Study (GINI), participants were randomly assigned to partial or complete cow's milk formula, if they were not going to exclusively breast-feed. The incidence of AD was compared.
The quality of evidence for whether breast-feeding reduces the likelihood of AD is low because there is only 1 fair-quality nonrandomized comparative study addressing this question, and the evidence from the study is conflicting. 5.3.3. Special diets in infants and young children5.3.3.1. Soy infant formula versus cow's milk infant formulaGuideline 38: The EP does not recommend using soy infant formula instead of cow's milk infant formula as a strategy for preventing the development of FA or modifying its clinical course in at-risk infants (“at risk” is defined in Guideline 32, section 5.2.1). Rationale: The literature reports little difference between soy infant formula and cow's milk infant formula for the prevention of FA in at-risk infants. Balance of benefits and harms: There appears to be neither long-term harm nor significant benefit in using soy infant formula. Quality of evidence: Moderate Contribution of expert opinion: Minimal Osborn and Sinn231 conducted a review to determine the effect of feeding adapted soy infant formula compared with human milk, hydrolyzed infant formulas, or cow's milk infant formula to infants who did not have a clinical FA in the first 6 months of life. They found 3 studies that compared soy infant formula with cow's milk infant formula. They reported no significant differences in incidence of childhood allergies, infant or childhood asthma, infant or childhood AD, or infant or childhood allergic rhinitis. 5.3.3.2. Hydrolyzed infant formulas versus cow's milk infant formula or breast-feedingGuideline 39: The EP suggests that the use of hydrolyzed infant formulas, as opposed to cow's milk formula, may be considered as a strategy for preventing the development of FA in at-risk infants who are not exclusively breast-fed (“at risk” is defined in Guideline 32, section 5.2.1). Cost and availability of extensively hydrolyzed infant formulas may be weighed as prohibitive factors. Rationale: Only a limited number of studies exist to indicate that extensively or partially hydrolyzed infant formulas reduce the development of CMA in at-risk infants. Balance of benefits and harms: The preventive effects of hydrolyzed infant formulas on allergy in infants and children vary considerably from study to study. Evidence from a small number of large-population studies shows that feeding hydrolyzed infant formulas, as compared with cow's milk infant formula, to at-risk infants may reduce, albeit to a small extent, allergy in infants and children and CMA in infants. None of the studies show reduction in allergy to foods other than cow's milk.232-235 Practical and cost considerations of extensively hydrolyzed infant formulas may limit their use to infants who are at risk and not being exclusively breast-fed. There is no evidence to suggest exclusive feeding with a hydrolyzed infant formula is more likely to prevent atopic disease than exclusive breast-feeding. The influence of duration of use on the effect of hydrolyzed infant formula on the development of allergy is not known. Quality of evidence: Moderate Contribution of expert opinion: Moderate The documented benefits of nutritional intervention that may prevent or delay the onset of atopic disease are largely limited to infants at risk of developing allergy. Current evidence does not support a major role for maternal dietary restrictions during pregnancy or lactation. There is evidence that breast-feeding for at least 4 months, compared with feeding formula made with intact cow's milk protein, prevents or delays the occurrence of AD, CMA, and wheezing in early childhood. In studies of infants who are at risk of developing atopy and not exclusively breastfed for 4 to 6 months, there is modest evidence that the onset of atopic disease (particularly AD) may be delayed or prevented by the use of hydrolyzed infant formulas, compared with formula made with intact cow's milk protein. Comparative studies of the various hydrolyzed formulas also indicate that not all formulas have the same protective benefit. There is also little evidence that delaying the timing of the introduction of complementary foods beyond 4 to 6 months of age prevents the occurrence of atopic disease. At present, there are insufficient data to document a protective effect of any dietary intervention beyond 4 to 6 months of age for the development of atopic disease. Several studies have examined the effect of infant formulas and breast-feeding on the development of subsequent atopic disease. For example:
The EP found no information in the literature on the effects of specialized diets on overall growth and development. A summary of 5 RCTs that evaluated specialized infant formulas is provided in Appendix D, Table S-V. 5.3.4. Timing of introduction of allergenic foods to infantsGuideline 40: The EP suggests that the introduction of solid foods should not be delayed beyond 4 to 6 months of age. Potentially allergenic foods may be introduced at this time as well. Rationale: Insufficient evidence exists for delaying introduction of solid foods, including potentially allergenic foods, beyond 4 to 6 months of age, even in infants at risk (as defined in Guideline 32, section 5.2.1) of developing allergic disease. Balance of benefits and harms: Restricting exposure to food antigens during infancy has been hypothesized as a means of preventing development of FA. However, restricting developmentally appropriate solid food variety beyond age 6 months can lead to inadequate nutrient intake, growth deficits, and feeding problems. Quality of evidence: Low Contribution of expert opinion: Significant Several guidelines developed by other organizations recommend delaying the introduction of solid foods to infants for 4 or 6 months after birth in an effort to prevent atopic disease.78,237-240 However, no clear consensus exists regarding the risks and benefits of delaying the introduction of solid foods in infants beyond 4 to 6 months after birth. The EP identified the following 2 studies that evaluated the effect of breast-feeding in combination with delayed introduction of solid foods in infants at risk for all allergies.
In a comparative study of more than 900 families by Venter et al,243 introduction of solid foods after weaning or after 16 weeks increased the likelihood of FA at 1 and 3 years (p = 0.02 for both ages). The quality of evidence for when to introduce allergenic solid foods to infants is low, given that only 2 controlled trials of relatively low quality address it. No controlled studies have addressed delayed introduction of solid foods in children who are not at risk for atopic disease. 5.4. Knowledge gapsWith the lack of large numbers of well-controlled studies in managing and preventing FA, there are several areas where expert opinion was important in making either recommendations or suggestions. These areas, in need of further research, include:
6. Diagnosis and Management of Food-Induced Anaphylaxis and other Acute Allergic Reactions to FoodsThis section of the Guidelines focuses on the diagnosis and management of food-induced anaphylaxis that arises through IgE-mediated immune mechanisms. Food-induced anaphylaxis is a potentially fatal disorder and, like other forms of anaphylaxis, is increasing in incidence in industrialized countries.30,42,244-247 Although food-induced anaphylaxis is not always easily recognized, the early recognition of specific signs and symptoms associated with a reaction, the timing of the reaction, and the existence of concomitant factors and disease processes help make the diagnosis. Prompt recognition and management are essential to ensure a good outcome.12 Anaphylaxis is significantly under-recognized and under-treated.244-246,248 One possible reason for this is the failure to appreciate that anaphylaxis can present without obvious cutaneous symptoms, which happens in 10% to 20% of cases, or without overt shock. The systematic review of the literature on food-induced anaphylaxis found a paucity of studies meeting standards for inclusion in these Guidelines. Thus, the evidence base for the recognition, diagnosis, and especially the management of food-induced anaphylaxis is significantly limited. Consequently, the EP supplied much of this section's information and provided literature based on individual citations deemed to be relevant and their own experience. In addition, much of this information is gleaned from the available literature related to anaphylaxis in general and applied specifically to FA. 6.1. Definition of anaphylaxisAnaphylaxis is defined as a serious allergic reaction that is rapid in onset and may cause death.245,249 Typically, IgE-mediated food-induced anaphylaxis is believed to involve systemic mediator release from sensitized mast cells and basophils.250 The term anaphylactoid has been used in the past to indicate adverse reactions that are not IgE mediated and typically are not life-threatening. This term is imprecise and will not be used in these Guidelines. 6.2. Diagnosis of acute, life-threatening, food-induced allergic reactionsGuideline 41: The EP recommends that the health care professional considering a diagnosis of food-induced anaphylaxis should understand:
Rationale: The evidence and expert opinion support prompt recognition and diagnosis of food-induced anaphylaxis. Balance of benefits and harms: Prompt recognition and diagnosis of food-induced anaphylaxis are essential and necessary to ensure appropriate health outcomes and to prevent progression to life-threatening reactions. Potential harm, including the possibility of death, exists if the diagnosis is delayed or not recognized. Quality of evidence: Low Contribution of expert opinion: Significant The diagnosis of anaphylaxis in general is based on clinical findings and a detailed description of the acute episode. Food-induced anaphylaxis also includes the association with known or suspected food exposure. The contribution of laboratory testing to the diagnosis of anaphylaxis is minimal, except where it may be important to diagnose the condition of FA. The most common food triggers for anaphylaxis are peanut, tree nuts, milk, egg, fish, and crustacean shellfish. The incidence is variable depending on age, regional diets, food preparation, amount of exposure, and timing of first exposure.153,251 A review of findings from administrative databases and acute-care settings38,40-42,252-257 shows that association with a specific food is reported in up to 80% of anaphylaxis cases. The patient's medical history is essential in establishing a diagnosis of food-induced anaphylaxis. A history of prior food-induced allergic reactions or prior diagnosis of FA (as defined in section 4) in association with known ingestion of a food protein aids in making a diagnosis. However, anaphylaxis in association with first-time food ingestion can occur at any age and is more common in young children. Studies have shown that 20% of episodes of anaphylaxis in the school setting occur with exposure to a food for the first time.258 6.2.1. Diagnostic criteria for anaphylaxisNew diagnostic criteria for anaphylaxis were published in 200612 to help health care professionals both recognize the spectrum of signs and symptoms that constitute anaphylaxis and establish a more systematic approach to its diagnosis and management. The following 3 criteria were established, and the presence of any 1 of these criteria indicates that anaphylaxis is highly likely:
Note: In infants and young children, hypotension may be a late manifestation of hypovolemic shock. Tachycardia, in the absence of hypotension, also may indicate shock.259 6.2.2. Signs and symptoms of food-induced anaphylaxisUsually, anaphylaxis involves more than 1 organ system, which helps distinguish it from other acute reactions such as asthma exacerbations, respiratory symptoms, urticaria/angioedema, or GI symptoms. The signs and symptoms for anaphylaxis in general are the same for food-induced anaphylaxis12,247,251,260-262 and include:
6.2.3. Time course of food-induced anaphylaxisFood-induced anaphylaxis is typically characterized by a defined exposure to a food allergen that is followed by a rapid onset and evolution of symptoms over minutes to several hours. Deaths from food-induced anaphylaxis have been reported within 30 minutes to 2 hours of exposure71,72,263 and usually result from cardiorespiratory compromise.251 Food-induced anaphylaxis also can have a milder course and resolve spontaneously, most likely due to endogenous production of vasoconstrictors (for example, epinephrine, endothelin, angiotensin II, and others).261,264,265 The time course of an anaphylactic reaction may be uniphasic, biphasic, or protracted. Each is defined as follows:
Fatalities associated with food-induced anaphylaxis are most commonly associated with peanut or tree nut ingestion.71,72,263 Such fatalities are associated with delayed use or lack of proper epinephrine dosing. The highest risk groups for fatal anaphylaxis associated with food ingestion are:
6.2.4. Comorbid diseases and factors that increase the risk of food-induced anaphylaxisComorbidities may affect symptom severity and treatment response in patients with food-induced anaphylaxis.261,262,264,268
Certain medications also may affect symptom severity and treatment response in patients with food-induced anaphylaxis, for example:
6.2.5. Other diseases associated with acute reactions to foodSeveral other FA disorders, both IgE and non-IgE mediated, described in detail in sections 2, 3, and 4, may have acute symptoms after food ingestion. Some disorders share IgE-mediated mechanisms such as localized urticaria or angioedema, generalized flushing, OAS, and food-dependent exercise-induced anaphylaxis and may progress to life-threatening anaphylaxis. Other non-IgE-mediated disorders such as FPIES and AP may present with acute, repetitive GI symptoms. In particular, FPIES may be confused with anaphylaxis because, minutes to hours after food or formula ingestion, patients often develop repetitive emesis in association with pallor, diarrhea, lethargy, and hypotension due to massive intravascular fluid shifts. Patients with FPIES require treatment via aggressive fluid resuscitation and possibly corticosteroids. These patients typically do not respond to epinephrine, in contrast to patients with acute reactions due to IgE-mediated disease. 6.2.6. Value of laboratory testing in the acute settingLaboratory testing is of limited value while a patient is experiencing an anaphylaxis reaction when immediate treatment is paramount. However, the diagnosis of food-induced anaphylaxis may be supported by tests that identify sensitization to the suspect food allergen. The diagnosis is rarely supported by tests that document elevated mast cell and basophil mediators, including plasma histamine and serum or plasma total tryptase.273-277 The use of these assays to diagnose food-induced anaphylaxis is unrealistic86,275,276,278 because (1) histamine is very labile and samples require special handling prior to processing and (2) tryptase lacks specificity and is not typically elevated in food-induced anaphylaxis. However, in a case of suspected anaphylaxis, elevated serum tryptase or urinary histamine levels may confirm the diagnosis of anaphylaxis unrelated to food (or possibly systemic mastocytosis). A negative tryptase finding also does not rule out food-induced anaphylaxis. Epicutaneous skin prick testing (section 4.2.2.1) and serum allergen-specific IgE testing (for example, ImmunoCAP) may provide information regarding a specific FA (section 4.2.2.4), but do not yield information about the cause of or risk for anaphylaxis. Rather, these tests evaluate allergen sensitization, while other tests (such as DBPCFC) determine clinical allergy (section 4.2.2.8). Correlation of testing with timing of ingestion and associated reaction, symptom profile, and response to therapy are important to make a definitive diagnosis. Additionally, no tests are available to predict severity of IgE-mediated reactions. 6.3. Treatment of acute, life-threatening, food-induced allergic reactions6.3.1. First-line and adjuvant treatment for food-induced anaphylaxisGuideline 42: The EP recommends that treatment for food-induced anaphylaxis should focus on the following:
Rationale: Evidence supports the implementation of rapid response and treatment for food-induced anaphylaxis and the use of IM epinephrine as first-line therapy. Balance of benefits and harms: The benefits of appropriate treatment for anaphylaxis begin with IM epinephrine injection. Benefits of epinephrine treatment far outweigh the risks of unnecessary dosing. Delays in instituting therapy with epinephrine are associated with risks of death and morbidity. Quality of evidence: Moderate Contribution of expert opinion: Significant As in all cases of anaphylaxis, whether food induced or not, prompt assessment and treatment are critical. Failure to respond promptly can result in rapid decline and death within 30-60 minutes.72,257,263,269,280,281 Epinephrine is the first-line treatment in all cases of anaphylaxis. All other drugs have a delayed onset of action. When there is suboptimal response to the initial dose of epinephrine, or if symptoms progress, repeat epinephrine dosing remains first-line therapy over adjunctive treatments. The cornerstones of initial management should begin with the following concurrent steps:282
These actions should be quickly followed by these additional steps:279,283-285
Administer epinephrine as soon as possible once anaphylaxis is recognized, and transport the patient to the nearest emergency facility. Delayed administration of epinephrine has been implicated in contributing to fatalities.71,72,86,263 In a study of 13 fatal or near-fatal food-induced anaphylactic reactions in children, 6 of the 7 children who survived received epinephrine within 30 minutes of ingesting the food, whereas only 2 of the 6 children who died received epinephrine within the first hour.72 Similar outcomes have been found in a fatal anaphylaxis registry71,263 established through the American Academy of Allergy, Asthma, and Immunology with the assistance of the Food Allergy and Anaphylaxis Network. Epinephrine, therefore, should be available at all times to patients at risk. A recent study in schools also highlights the fact that children with FA often do not have ready access to epinephrine at school, thus placing them at increased risk.286 Pharmacologic treatment of food-induced anaphylaxis is based on extrapolation from therapies used in cardiac arrest and asthma, from uncontrolled human trials of anaphylaxis during insect sting challenges, and from studies of anaphylaxis in animal models.245 RCTs that meet current standards have not been performed for any therapeutic interventions during anaphylaxis in humans. Placebo-controlled trials for epinephrine use have not been performed during anaphylaxis and likely will never be performed due to ethical considerations regarding a disease that can kill within minutes and requires prompt intervention.287 The evidence base for the pharmacologic management of an acute anaphylaxis episode has been extensively studied in 3 Cochrane collaborative reviews.288-290 Although these reviews do not include any RCTs on epinephrine use in anaphylaxis, they do highlight that epinephrine has been relatively well-investigated in:
Experts in the field agree that epinephrine is the only first-line treatment for anaphylaxis. There is no substitute for epinephrine, thus all other treatments are adjunctive. In the treatment of anaphylaxis, H1 and H2 antihistamines and corticosteroids are commonly used, but little or no data exist demonstrating their functional role or effectiveness. In summary: The use of antihistamines is the most common reason reported for not using epinephrine265 and may place a patient at significantly increased risk for progression toward a life-threatening reaction. 6.3.1.1. Epinephrine—first-line treatmentEpinephrine is the drug of choice for anaphylaxis and should be administered as first-line therapy. The pharmacologic actions of this agent address the pathophysiologic changes that occur in anaphylaxis better than any other single drug. Failure to administer epinephrine early in the course of treatment has been repeatedly implicated in anaphylaxis fatalities.71,72,244,247,248,263,291 Despite this fact, physicians often fail to prescribe epinephrine. In addition, the timing of emergency responses can determine when epinephrine is injected.40,65,245,265,292 The therapeutic actions of epinephrine, which encompass a broad range of effects germane to the mechanisms of anaphylaxis, include the following:285
Epinephrine has a narrow toxic-therapeutic index (risk-to-benefit ratio). In therapeutic doses and by any route, epinephrine frequently causes mild transient adverse effects in individuals of all ages. These include anxiety, fear, restlessness, headache, dizziness, palpitations, pallor, and tremor.285 Rarely, epinephrine may lead to ventricular arrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in BP, and intracranial hemorrhage.285 These severe adverse effects are more likely to occur when epinephrine is given in overdose by any route; for example, after an intravenous bolus injection or intravenous injection of a 1:1,000 epinephrine solution instead of a 1:10,000 epinephrine solution. Epinephrine has an onset of action within minutes but is rapidly metabolized. Therefore, the effect is often short-lived and repeated doses may be necessary.265,293,294 If a patient responds poorly to the initial dose or has ongoing or progressive symptoms despite initial dosing, repeated dosing may be required after 5 to 15 minutes. Reports of patients receiving epinephrine for food-induced or nonfood-induced anaphylaxis293,294 note that as high as 10% to 20% of individuals who receive epinephrine will require more than 1 dose before recovery of symptoms. In many of the cases, the subsequent doses of epinephrine were given more than 15 minutes after the first dose (some more than 1 hour), despite recommendations to repeat dosing as frequently as every 5 to 15 minutes. The optimal dosing interval for repeated dosing has not been studied prospectively. Epinephrine can be delivered through a variety of routes, including IM, IV, and endotracheal or intraosseous.284
6.3.1.2. Adjunctive treatment (pharmacologic and other)Note: These treatments often occur concomitantly, and are not meant to be sequential, with the exception of epinephrine as first-line treatment.
H1 antihistamines are useful only for relieving itching and urticaria. They do not relieve stridor, shortness of breath, wheezing, GI symptoms, or shock. Therefore, they should be considered adjunctive therapy and should not be substituted for epinephrine.71,72,254,263,281,288,298 For oral and IV dosing, first-generation H1 antihistamines such as diphenhydramine 25-50 mg are used. Sedation and cognitive and psychomotor impairment are recognized side effects of the first-generation H1 antihistamines, and these may contribute to decreased awareness of anaphylaxis symptoms.288,298 Alternative oral dosing with a less-sedating, second-generation H1 antihistamine (such as cetirizine 10 mg) may be used because it has a relatively rapid onset of action compared with other second-generation H1 antihistamines and is available in generic formulations.
6.3.2. Treatment of refractory anaphylaxisNo published prospective studies exist on the optimal management of refractory anaphylactic shock. Repeated use of epinephrine, as well as IV fluids, corticosteroids, and vasopressor agents, may be needed.260 Prompt transfer to an acute-care facility and ICU for treatment and monitoring is essential. 6.3.3. Possible risks of acute therapy for anaphylaxisThere are no absolute contraindications to epinephrine use in anaphylaxis.260,276 However, there are subgroups of patients who might theoretically be at higher risk for adverse effects during epinephrine therapy. Because the risk of death or serious disability from anaphylaxis itself usually outweighs other concerns,260,276 existing evidence clearly favors the benefit of epinephrine administration in most situations. Some level of decision making regarding the risk-to-benefit ratio may be warranted, and especially for patients:
6.3.4. Treatment to prevent biphasic or protracted food-induced allergic reactionsVery little information exists that defines the mechanism of biphasic or protracted allergic reactions. Similarly, little information exists to support specific therapy to prevent biphasic or protracted food-induced allergic reactions. In general, induction and recruitment of inflammatory cells and release of preformed, long-acting mediators from mast cells have been implicated as mechanisms.267 Due to their anti-inflammatory properties, systemic corticosteroids are often recommended to prevent biphasic or protracted food-induced allergic reactions, but little data support their use. 6.3.5. Management of milder, acute food-induced allergic reactions in health care settingsMilder forms of allergic reactions, such as flushing, urticaria, isolated mild angioedema, or symptoms of OAS, can be treated with H1 and H2 antihistamine medications.153,299 When antihistamines alone are given, ongoing observation and monitoring are warranted to ensure a lack of progression to more significant symptoms of anaphylaxis. If progression or increased severity is noted, epinephrine should be administered immediately. Additionally, if there is a history of a prior severe allergic reaction, epinephrine should be administered promptly and earlier in the course of treatment (for example, at the onset of even mild symptoms). 6.4. Management of food-induced anaphylaxisGuideline 43: The EP recommends that the management of food-induced anaphylaxis should focus on the following:
Rationale: Despite the lack of evidence, the EP recommends close monitoring, scheduled follow-up, and patient education for effective management following anaphylaxis. Balance of benefits and harms: The benefits of appropriate management following food-induced anaphylaxis should serve to further protect the patient through long-term follow-up care and education, with the benefit of preventing subsequent events. The potential harm is minimal if appropriate education is employed. Quality of evidence: Low Contribution of expert opinion: Significant 6.4.1. Observation periodThere is no consensus in the literature regarding the optimal amount of time that a patient who has been successfully treated for anaphylaxis should be observed prior to discharge. All patients who receive epinephrine for food-induced anaphylaxis should proceed to an emergency facility for observation and possibly additional treatment. A reasonable length of time for observation of most patients who have experienced anaphylaxis is 4 to 6 hours, with prolonged observation times or hospital admission for patients with severe or refractory symptoms.249,262 6.4.2. Discharge plan following treatment for food-induced anaphylaxisAll patients who have experienced anaphylaxis should be sent home with the following:
The treating health care professional should consider referral of the patient to a specialist such as an allergist/immunologist for further evaluation. 6.4.2.1. Anaphylaxis emergency action planPatients should be given a written anaphylaxis emergency action plan that contains information about self-injection of epinephrine prior to discharge261,303 (see sample action plan in Appendix E). Patients should be instructed on the value of medical identification jewelry to easily identify themselves as patients with anaphylaxis potential and their food allergen triggers. 6.4.2.2. Epinephrine auto-injector (or 2-dose prescription)All patients experiencing anaphylaxis should be provided directly with an epinephrine auto-injector or, if this is not possible, with a prescription (recommended prescription is for 2 doses of epinephrine), and advised to fill it immediately. Other patients who should be prescribed an epinephrine auto-injector include:
In addition, consideration should be given to prescribing an epinephrine auto-injector for all patients with FA having IgE-mediated reactions because it is impossible to predict the severity of any subsequent reactions with accuracy. Instructions in the proper use of epinephrine auto-injectors should be reviewed verbally with the patient and accompanied by a DVD (if available) and a written anaphylaxis emergency action plan. Special care should be taken to explain the importance of carrying epinephrine at all times and on advising the patient to make sure that family and friends are aware of the risks of anaphylaxis, the patient's triggers, and how to administer epinephrine. Where allowed by state law, students should be advised to carry their epinephrine auto-injector at school and at all school-related events and activities and to self-administer when needed. 6.4.2.3. Plan for monitoring auto-injector expiration datesPatients and family members should be advised to regularly check the epinephrine auto-injector expiration dates (these expire after 1 year) and to ensure that the color of the liquid within the device remains clear. Ideally, the prescribing physician's office should see patients annually or notify patients (or the family members of patients who are minors) by telephone or mail that their auto-injector will soon reach its expiration date and that the prescription should be renewed. Patients are also encouraged to register for automated pharmacy reminders for epinephrine renewal. Epinephrine auto-injectors are temperature sensitive and should be stored at room temperature to prevent degradation of the medication. 6.4.2.4. Plan for arranging further evaluationAdvice should be provided to the patient regarding follow-up with his or her primary health care professional within 1 to 2 weeks after a food-induced anaphylaxis event. Additional information may be needed about obtaining a referral to a specialist such as an allergist/immunologist for testing, diagnosis, and ongoing management of the allergy. Direct communication between the treating physician and the primary health care professional is recommended to ensure that appropriate follow-up is attained. 6.4.2.5. Printed information about anaphylaxis and its treatmentThe emergency doctor, treating physician, or health care professional should give the patient who has been treated for anaphylaxis and is subsequently leaving the emergency department or hospital printed information about anaphylaxis and its treatment.304 The mnemonic “SAFE” has been developed to remind health care professionals of the 4 basic action steps suggested for these patients.304 The SAFE (Seek support, Allergen identification and avoidance, Follow up with specialty care, Epinephrine for emergencies) counseling is outlined below and has been incorporated within printable patient information materials.
Other sources of accurate patient information, accessible through the Internet, include the American Academy of Allergy, Asthma and Immunology (www.aaaai.org) and the American College of Allergy, Asthma and Immunology (www.acaai.org). 6.5. Knowledge gapsDue to a lack of controlled studies in the area of food-induced anaphylaxis management, significant knowledge gaps exist in several areas, including:
AcknowledgmentsSources of funding: J. A. Boyce has served on the Advisory Board of GlaxoSmithKline. He has served as a consultant and/or speaker for Altana, GlaxoSmithKline, and Merck. He has received funding/grant support from the National Institutes of Health. A. Assa'ad holds, or is listed as an inventor on, US patent application #10/566903, entitled “Genetic markers of food allergy.” She has served as a consultant for GlaxoSmithKline and as a speaker for the American College of Allergy, Asthma, and Immunology, the North East Allergy Society, the Virginia Allergy Society, the New England Allergy Society, and the American Academy of Pediatrics. Dr Assa'ad has received funding/grant support from GlaxoSmithKline. A. W. Burks holds, or is listed as an inventor on, multiple US patents related to food allergy. He owns stock in Allertein and MastCell, Inc, and is a minority stockholder in Dannon Co Probiotics. He has served as a consultant for ActoGeniX NV, McNeil Nutritionals, Mead Johnson, and Novartis. He has served on the speaker's bureau for EpiPen/Dey, LP, and has served on the data monitoring committee for Genentech. He has served on an expert panel for Nutricia. Dr Burks has received funding/grant support from the Food Allergy and Anaphylaxis Network, Gerber, Mead Johnson, and the National Institutes of Health. S. M. Jones has served as a speaker and grant reviewer and has served on the medical advisory committee for the Food Allergy and Anaphylaxis Network. She has received funding/grant support from Dyax Corp, the Food Allergy and Anaphylaxis Network, Mead Johnson, the National Peanut Board, and the National Institutes of Health. H. A. Sampson holds, or is listed as an inventor on, multiple US patents related to food allergy. He owns stock in Allertein Therapeutics. He is the immediate past president of the American Academy of Allergy, Asthma, and Immunology. He has served as a consultant for Allertein Therapeutics, the American Academy of Allergy, Asthma, and Immunology, the Food Allergy Initiative, and Schering Plough. He has received funding/grant support for research projects from the Food Allergy Initiative, the National Institutes of Health (Division of Receipt and Referral, National Institute of Allergy and Infectious Diseases, National Center for Complementary and Alternative Medicine), and Phadia AB. He is a co-owner of Herbal Spring, LLC. R. A. Wood has served as a speaker/advisory board member for GlaxoSmithKline, Merck, and Dey. He has received funding/grant support from Genentech and the National Institutes of Health (National Institute of Allergy and Infectious Diseases). S. H. Arshad has received funding/grant support from the National Institutes of Health and the National Institute of Health Research, UK. S. L. Bahna has received funding/grant support from Genentech. L. A. Beck has received funding/grant support from the American Academy of Allergy, Asthma, and Immunology, the National Eczema Association, and the National Institutes of Health. C. Byrd-Bredbenner owns stock in Johnson & Johnson. She has received funding/grant support from the US Department of Agriculture, the Canned Food Alliance, and the New Jersey Department of Health and Senior Services. C. A. Camargo Jr has consulted for Dey and Novartis. He has received funding/grant support from a variety of government agencies and not-for-profit research foundations, as well as Dey and Novartis. L. Eichenfield has received funding/grant support from a variety of not-for-profit foundations, as well as Astellas, Ferndale, Johnson & Johnson, Novartis, Sinclair, Stiefel, and Therapeutics Inc. G. T. Furuta has served as a consultant and/or speaker to Ception Therapeutics and TAP. He has received funding/grant support from the American Gastrointestinal Association and the National Institutes of Health. J. M. Hanifin has served as served as a consultant for ALZA, Anesiva, Inc, Barrier Therapeutics, Inc, Milliken & Company, Nordic Biotech, Novartis Pharmaceuticals Corporation, Shionogi USA, Taisho Pharmaceutical R&D, Inc, Teikoku Pharma USA, Inc, UCB, York Pharma, ZARS, Inc, and ZymoGenetics. He has served as an investigator or received research funding from ALZA, Astellas Pharma US, Inc, Asubio Pharmaceuticals, Inc, Centocor, Inc, Corgentech, Novartis, Nucryst Pharmaceuticals, Seattle Genetics, and Shionogi USA. M. Kraft has served as a consultant and/or speaker for Astra-Zeneca, Genentech, GlaxoSmithKline, Merck, Novartis, and Sepracor. She has received funding/grant support from Genentech, GlaxoSmithKline, the National Institutes of Health and Novartis. B. D. Levy holds, or is listed as an inventor on, US patent applications #20080064746 entitled “Lipoxins and aspirin-triggered lipoxins and their stable analogs in the treatment of asthma and inflammatory airway diseases” and #20080096961 entitled “Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma.” He owns stock in Resolvyx Pharmaceuticals. He has served as a consultant for Bayer Healthcare and Resolvyx Pharmaceuticals. Dr Levy has received funding/grant support from the National Institutes of Health. P. Lieberman has served as a consultant and/or speaker to Dey Laboratories, Novartis, Schering-Plough, AstraZenica, Merck, TEVA, Pfizer, MEDA, Alcon, Genentech, Intelliject, and the Food Allergy and Anaphylaxis Network. He is past president of the American Academy of Allergy, Asthma, and Immunology. L. C. Schneider has served as a consultant/clinical advisor for the Food Allergy Initiative. She has received funding/grant support from a variety of not-for-profit research foundations, as well as Novartis and the National Institutes of Health. R. A. Simon has served as a speaker for Dey Laboratories, Genentech, GlaxoSmithKline, Merck, Novartis, and the US Food and Drug Administration. F. E. R. Simons holds a patent on “Fast-disintegrating epinephrine tablets for sublingual administration.” She is a past-president of the American Academy of Allergy, Asthma, and Immunology and of the Canadian Society of Allergy and Clinical Immunology. She is a member of the advisory boards of Dey, Intelliject, and ALK-Abello. She has received funding/grant support from AllerGen, the Canadian Allergy, Asthma and Immunology Foundation/Anaphylaxis Canada, and the Canadian Institutes of Health Research. S. J. Teach has served as a speaker for AstraZeneca. He has received funding/grant support from the AstraZeneca Foundation, Aventis, the Child Health Center Board, the CNMC Research Advisory Council, the National Association of Chain Drug Stores Foundation, the National Institutes of Health (National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute), Novartis/Genentech, the Robert Woods Johnson Foundation, the US Centers for Disease Control and Prevention, the US Public Health Service, and the Washington, DC, Department of Health. Abbreviations
Appendix A. Coordinating Committee Member Organizations and RepresentativesAgency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov/ Stephanie Chang, MD, MPH Allergy & Asthma Network Mothers of Asthmatics (AANMA) http://www.aanma.org/ Nancy Sander Sandra J. Fusco-Walker (alternate*) American Academy of Allergy, Asthma & Immunology (AAAAI) http://www.aaaai.org/ Hugh A. Sampson, MD American Academy of Dermatology (AAD) http://www.aad.org/ Lawrence F. Eichenfield, MD, FAAD American Academy of Emergency Medicine (AAEM) http://www.aaem.org/ Joseph P. Wood, MD, JD American Academy of Pediatrics (AAP) http://www.aap.org/ Scott Sicherer, MD, FAAP American Academy of Physician Assistants (AAPA) http://www.aapa.org/ Bob McNellis, MPH, PA American College of Allergy, Asthma and Immunology (ACAAI) http://www.acaai.org/ Sami Bahna, MD, DrPH American College of Emergency Physicians (ACEP) http://www.acep.org/ Wyatt W. Decker, MD American College of Gastroenterology (ACG) http://www.acg.gi.org/ Steven J. Czinn, MD Dawn L. Francis, MD American College of Physicians (ACP) http://www.acponline.org/ Raymond J. Dattwyler, MD American Dietetic Association (ADA) http://www.eatright.org/ Marianne Smith Edge American Nurses Association (ANA) http://www.nursingworld.org/ Karen Huss, PhD, RN, APRN-BC American Partnership for Eosinophilic Disorders (APFED) http://www.apfed.org/ Beth Mays Wendy Book (alternate) American Society for Nutrition (ASN) http://www.nutrition.org/ George J. Fuchs III, MD American Thoracic Society (ATS) http://www.thoracic.org/ Joel N. Kline, MD, MSc Asthma and Allergy Foundation of America (AAFA) http://www.aafa.org/ Charlotte Collins, JD Mary Brasler, MSN, EdD Centers for Disease Control and Prevention (CDC) http://www.cdc.gov/ Thomas Sinks, PhD Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) http://www.nichd.nih.gov/ Gilman Grave, MD European Academy of Allergy and Clinical Immunology (EAACI) http://eaaci.net/ Nikolaos G. Papadopoulos, MD, PhD Antonella Muraro, MD, PhD Food Allergy & Anaphylaxis Network (FAAN) http://www.foodallergy.org/ Julia E. Bradsher, PhD, MBA Anne Muñoz-Furlong Food Allergy Initiative (FAI) http://www.faiusa.org/ Mary Jane Marchisotto Robert Pacenza David Bunning Inflammatory Skin Disease Institute (ISDI) http://www.isdionline.org/ LaDonna Finch National Association of School Nurses (NASN) http://www.nasn.org/ Donna Heller, MS, RN, NCSN National Eczema Association (NEA) http://www.nationaleczema.org/ Julie Block National Heart, Lung, and Blood Institute (NHLBI) http://www.nhlbi.nih.gov/ Virginia Taggart, MPH National Institute of Allergy and Infectious Diseases (NIAID) http://www.niaid.nih.gov/ Daniel Rotrosen, MD Matthew J. Fenton, PhD Dean D. Metcalfe, MD Marshall Plaut, MD Alkis Togias, MD National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) http://www.niddk.nih.gov/ Frank A Hamilton, MD National Institute of Nursing Research (NINR) http://www.ninr.nih.gov/ Karen Huss, PhD, RN, APRN-BC National Institutes of Health Division of Nutrition Research Coordination (NIH DNRC) http://dnrc.nih.gov/ Van Hubbard, MD, PhD Margaret A. McDowell, PhD, MPH, RD Jean Pennington PhD, RD North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) http://www.naspghan.org/ Barry K. Wershil, MD Society for Pediatric Dermatology (SPD) http://www.pedsderm.net/ James Bergman, MD Society of Pediatric Nurses (SPN) https://www.pedsnurses.org/ Kathleen McCall, BSN, RN United States Department of Agriculture (USDA) http://www.usda.gov/ David M. Klurfeld, PhD United States Environmental Protection Agency (EPA) http://www.epa.gov/ John Kough, PhD MaryJane Selgrade, PhD United States Food and Drug Administration (FDA) (observer organization) http://www.fda.gov/ Badrul A. Chowdhury, MD, PhD Jay E. Slater, MD Ronald L. Rabin, MD *The person who represented the organization on the CC when the primary representative was unable to attend. Appendix B. Expert Panel MembersChair Joshua A. Boyce, MD Associate Professor of Medicine Harvard Medical School Specialty: Allergy/pediatric pulmonology Panelists S. Hasan Arshad, MBBS, MRCP, DM, FRCP Chair in Allergy and Clinical Immunology University of Southampton Specialty: Allergy/epidemiology Amal Assa'ad, MD Professor of Pediatrics Director, Allergy and Immunology Fellowship Associate Director, Division of Allergy and Immunology Cincinnati Children's Hospital Medical Center Specialty: Allergy/pediatrics Sami L. Bahna, MD, DrPH Professor of Pediatrics and Medicine Chief, Allergy and Immunology Section Louisiana State University Health Sciences Center-Shreveport Specialty: Allergy Lisa A. Beck, MD Associate Professor of Dermatology, Director of Translational Research University of Rochester Medical Center Specialty: Dermatology A. Wesley Burks, MD Professor, Department of Pediatrics Duke University Specialty: Allergy/pediatrics Carol Byrd-Bredbenner, PhD, RD, FADA Professor of Nutrition/Extension Specialist Rutgers, The State University of New Jersey Specialty: Nutrition/education Carlos A. Camargo, MD, DrPH Director, EMNet Coordinating Center Massachusetts General Hospital Harvard Medical School Specialty: Epidemiology/emergency medicine Lawrence Eichenfield, MD Professor, Department of Pediatrics and Medicine University of California, San Diego School of Medicine Director, Children's Specialists of San Diego Rady Children's Hospital, San Diego Specialty: Dermatology/pediatrics Glenn T. Furuta, MD Professor of Pediatrics University of Colorado Denver, School of Medicine Specialty: Gastroenterology/pediatrics Jon M. Hanifin, MD Professor of Dermatology Oregon Health and Science University Specialty: Dermatology Carol Jones, RN, AE-C Certified Asthma Nurse Educator and Consultant Specialty: Nursing/education Stacie M. Jones, MD Professor of Pediatrics, Chief of Allergy/Immunology University of Arkansas for Medical Sciences and Arkansas Children's Hospital Specialty: Allergy/pediatrics Monica Kraft, MD Professor of Medicine Director, Duke University Asthma, Allergy and Airway Center Vice Chair for Research, Department of Medicine Duke University Medical Center Specialty: Pulmonology/internal medicine/critical care Bruce D. Levy, MD Assistant Professor in Medicine Pulmonary and Critical Care Medicine Division Brigham and Women's Hospital Specialty: Pulmonology Phil Lieberman, MD Clinical Professor of Medicine, Division of Allergy and Immunology Clinical Professor of Pediatrics University of Tennessee Specialty: Allergy Stefano Luccioli, MD Senior Medical Advisor Office of Food Additive Safety, Center for Food Safety and Applied Nutrition US Food and Drug Administration Specialty: Allergy/internal medicine Kathleen M. McCall, BSN, RN Case Manager, Primary Care Children's Hospital of Orange County Specialty: Nursing Hugh A. Sampson, MD Professor of Pediatrics Mount Sinai School of Medicine Specialty: Allergy/pediatrics Lynda C. Schneider, MD Director, Allergy Program, Director, Atopic Dermatitis Center Children's Hospital, Boston Associate Professor of Pediatrics Harvard Medical School Specialty: Allergy/pediatrics Ronald A. Simon, MD Head, Division of Allergy, Asthma and Immunology Adjunct Professor, Department of Molecular and Experimental Medicine The Scripps Research Institute Specialty: Allergy/internal medicine F. Estelle R. Simons, MD Professor, Department of Pediatrics and Child Health Professor, Department of Immunology University of Manitoba Specialty: Allergy/pediatrics Stephen J. Teach, MD, MPH Associate Chief, Division of Emergency Medicine Children's National Medical Center Specialty: Pediatrics/emergency medicine Robert A. Wood, MD Professor of Pediatrics Johns Hopkins University School of Medicine Specialty: Allergy/pediatrics Barbara P. Yawn, MD, MPH, MSc Director, Department of Research Olmsted Medical Center Specialty: Family medicine Appendix C. Understanding “Quality of the Body of Evidence”Quality is a technical term adopted by guidelines developers to describe the body of evidence used to develop a recommendation or guideline. The body of evidence refers to all the papers reviewed about a given clinical topic, for example, the prevalence of food allergies (FAs) or the effectiveness of immunotherapy. It usually is applied to a group of relevant papers, but in some cases could be applied to a single paper if that is the only one published on that topic. Quality is dependent on both objective features of the studies and their conclusions. The quality rating ultimately reflects the confidence in the literature under review. Objective features include the study population size, how the clinical trial was blinded (for example, no blinding, single-blinded, or double-blinded), and whether the trial was placebo-controlled. For example, a body of evidence obtained from randomized controlled trials (RCTs) is rated as high quality, whereas evidence obtained from observational studies is rated as low quality. However, if strong conclusions can be made from an observational study, this can raise the quality from “Low” to a higher grade (see below for the grading system used in these Guidelines). Quality also reflects the likelihood that the conclusions of the study or studies will affect the confidence of the recommendation being made and whether further research is likely to affect that confidence. For these Guidelines, RAND reviewed the available scientific literature and assessed the quality of the evidence relating to each key question provided by the Expert Panel and NIAID. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, RAND provided a grade of high, moderate, or low as a measure of the quality of evidence, according to the following criteria:
Assessment of the quality of evidence does not necessarily question the veracity of the scientific results in the papers reviewed, although serious limitations in study quality would result in a lowering of the quality grade. Similarly, the quality grade does not necessarily question the accuracy of the methods used to generate the scientific results. A guideline with a GRADE rating of “Low” indicates that the objective features of the relevant clinical studies were low. However, the conclusions of the studies are presumed to be correct (in the absence of clear bias, lack of appropriate contrails, or methodological deficiencies) and the data presumed to have been generated and reported accurately. Appendix D. Summary TablesTable S-IFood allergen cross-reactivity
Table S-IIPeanut allergy prevalence studies
Table S-IIITree nut allergy prevalence studies
Table S-IVUS studies of the natural history of EoE
Table S-VRCTs of specialized formulas for infants and young children
Appendix E. Sample Anaphylaxis Emergency Action PlanFootnotesDisclosure of potential conflict of interest The other authors have declared that they have no conflict of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Contributor InformationJoshua A. Boyce, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Department of Medicine Harvard Medical School, Boston, Mass. Amal Assa'ad, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. A. Wesley Burks, Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC. Stacie M. Jones, Division of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, Ark. Hugh A. Sampson, Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medicine, New York, NY. Robert A. Wood, Division of Allergy and Immunology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Md. Marshall Plaut, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Susan F. Cooper, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Matthew J. Fenton, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. S. Hasan Arshad, School of Medicine, University of Southampton, Southampton, UK, The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, UK, Southampton University Hospital NHS Trust, Southampton, UK. Sami L. Bahna, Department of Pediatrics, Section of Allergy and Immunology, Louisiana State University Health Sciences Center, Shreveport, La. Lisa A. Beck, Department of Dermatology, University of Rochester Medical Center, Rochester, NY. Carol Byrd-Bredbenner, Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ. Carlos A. Camargo, Jr, Department of Emergency Medicine, Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Lawrence Eichenfield, Division of Pediatric and Adolescent Dermatology, Rady Children's Hospital, San Diego, Calif, Departments of Pediatrics and Medicine, University of California, San Diego, San Diego, Calif. Glenn T. Furuta, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Digestive Health Institute, Children's Hospital Denver, Aurora, Colo, Department of Pediatrics, National Jewish Health, Denver, Colo, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colo. Jon M. Hanifin, Department of Dermatology, Oregon Health and Science University, Portland, Ore. Carol Jones, Asthma Educator and Consultant, Allergy and Asthma Network Mother's of Asthmatics, McLean, Va. Monica Kraft, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC. Bruce D. Levy, Partners Asthma Center, Pulmonary and Critical Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Phil Lieberman, Division of Allergy and Immunology, Department of Medicine, University of Tennessee College of Medicine, Memphis, Tenn. Stefano Luccioli, Office of Food Additive Safety, US Food and Drug Administration, College Park, Md. Kathleen M. McCall, Children's Hospital of Orange County, Orange, Calif. Lynda C. Schneider, Division of Immunology, Children's Hospital Boston, Boston, Mass. Ronald A. Simon, Division of Allergy, Asthma and Immunology, Scripps Clinic, San Diego, Calif. F. Estelle R. Simons, Departments of Pediatrics and Child Health and Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Stephen J. Teach, Division of Emergency Medicine, Children's National Medical Center, Washington, DC. Barbara P. 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Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr. 2008 Jun;138(6):1091–5. [PubMed] [Google Scholar] Which of the following is a characteristic of food allergy?The reaction can cause symptoms like hives, vomiting, belly pain, throat tightness, hoarseness, coughing, breathing problems, or a drop in blood pressure. Even if previous reactions have been mild, someone with a food allergy is always at risk for the next reaction being life-threatening.
What should be the first cereal introduced to an infant quizlet?Iron fortified cereal mixed with formula or breast milk is best 1st food. 8 teeth erupt between 6 and 12 mos; as baby begins to be able to chew, introduce semisolid foods to allow child to develop oral musculature, avoid rejection of textured foods later.
Which of the following foods should not be fed to infants because of the risk of botulism?The only known prevention measure for infant botulism is to avoid feeding honey to infants 12 months of age or less.
Which of the following should not be used to feed an infant under twelve months old )?honey until after a baby's first birthday. It can cause botulism in babies. unpasteurized juice, milk, yogurt, or cheese. regular cow's milk or soy drinks before 12 months instead of breast milk or formula.
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Of the following cereals, which is most likely to result in an allergic reaction upon first feeding?
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