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Introduction

FOOD ALLERGIES: CHARTING A ROADMAP TO SAFETY

Over the past 20 years, public concerns have grown in response to the apparent rising prevalence of food allergy and related atopic conditions,¹ such as eczema. Although evidence on the true prevalence of food allergy is complicated by insufficient or inconsistent data and studies with variable methodologies, many health care experts who care for patients agree that a real increase in food allergy has occurred and that it is unlikely to be due simply to an increase in awareness and better tools for diagnosis. Many stakeholders are concerned about these increases, including the general public, policy makers, regulatory agencies, the food industry, scientists, clinicians, and especially families of children and young people suffering from food allergy.

Food allergy has important implications not only for those individuals directly affected but also for their families, day care and school settings, and society (Gupta, 2014; Pawanker et al., 2011). Some children naturally grow out of a food allergy, while other children or adults develop a food allergy for the first time later in life. In either case, having a food allergy is a chronic disease that can influence a person’s quality of life throughout the lifespan and, in some unfortunate individuals, lead to death. The human stories of food-related anaphylaxis and the heavy burden of protecting children from foods that might initiate such serious allergic conditions are

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¹ The atopic conditions of childhood consist of the triad of asthma, allergic rhinitis, and atopic dermatitis. All share a common pathogenesis, being mediated by immunoglobulin E (IgE), and are frequently present together in the same individual and family.

particularly compelling. This burden includes fear of accidental consumption, difficulties with missing (or misunderstood) food labels, and bullying at school. Those not afflicted with such a disorder may have difficulty even imagining what life is like for severely food-allergic individuals, some of whom are allergic to multiple commonly encountered foods, such as milk, eggs, peanuts, tree nuts, and shellfish. To illustrate some of these issues, Box 1-1 includes real-life example statements from children, adolescents (DunnGalvin et al., 2009) and caretakers (Kahn, 2014; Monaco, 2015) as

they describe quality-of-life impacts and hazards of having a severe food allergy.

Ultimately, answering questions about the actual prevalence of food allergy, the mechanisms underlying allergen sensitization and the development of food allergy, and how to estimate the severity of disease in affected individuals, among many other research questions, requires adequate support from research funding sources. Similarly, protecting those with food allergy from accidental exposure and providing appropriate treatment for

those who develop reactions, demand effective governmental policy and consumer protections across multiple sectors, including agricultural production, the food industry, product labeling, regulatory authorities, and the food and entertainment industries. At the present time, however, despite a mounting body of data on the prevalence, health consequences, and associated costs of food allergy, this chronic disease has not garnered the level of societal attention that it warrants. Moreover, for patients and families at risk, recommendations and guidelines have not been clear about preventing exposure or the onset of reactions or for managing this disease.

In brief, the scientific knowledge about food allergy has significant gaps and, for those at risk, few or no reliable prevention strategies or treatments exist. How did we get to this situation? First, the accepted gold standard for identifying a food allergy—the oral food challenge (OFC)—has not been used widely due to difficulties of the procedure (e.g., risk of a severe reaction, length of procedure, the need to standardize the food), especially in research where large numbers of study participants are needed.

Second, conducting research on food allergy presents various types of practical barriers: studies are very costly due to the long duration of typical therapeutic studies (e.g., 2 to 4 years); the heterogeneity of participants; difficulty recruiting participants; and notably, too few research centers and researchers equipped to conduct high-quality studies.

Third, food allergy is a complicated, multifactorial disease and researchers do not fully understand its causes, mechanisms, and effects. Except for having atopic parents (i.e. parents with a predisposition to allergic reactions), the contributions of various factors to food allergy remain unclear and under investigation. Genetics, time, route of allergen exposure, diet, factors related to pregnancy and lactation, and the microbiome all are being studied as potential influences on the development of food allergy. The fact that food allergy develops in infants makes the research difficult, as conducting trials during pregnancy or in infants could be unethical.

Finally, few effective therapies for food allergy currently exist. The gaps in scientific understanding have impaired the development of effective therapies, although many promising ones are being investigated.

Professional medical associations continue to update their practice guidelines for food allergy despite limitations in the evidence, based on the most recent knowledge on diagnosis, prevention, treatment, and management. Yet, unlike other chronic diseases related to diet, such as diabetes or cardiovascular diseases, where specific strategies for prevention or management have been established (ADA, 2015; Goff et al., 2014), recommendations by governments or professional associations for preventing the onset of a food allergy have been hampered by limited or inconsistent data. Recent and ongoing research and clinical progress on assessment, diagnosis, and treatment of food allergy hold the promise of improving future practice

and management strategies. These advances include the safe use of OFCs as the gold standard for diagnosis, emerging data on the role of early exposure to potential allergens for favoring prevention, and high-quality studies of effective therapies. Indeed, based on the latest findings in food allergy prevention science, and particularly the latest findings on the protective effects of early exposure to peanut, leading organizations are rethinking the current recommendations and considering promising new approaches. Still, new thinking and approaches can have the unintended consequence of confusing parents and all the institutions that interact with people with food allergy, including schools, airlines, and restaurants.

For individuals who are already diagnosed, complete avoidance is still the only established method for preventing a reaction and, as indicated in Box 1-1, it is not easy to achieve. This is particularly the case when effective policies and practices are not implemented in places where foods are purchased or consumed (e.g., the hospitality and food service industries). Likewise, policies to ensure that relevant settings are prepared to identify and treat a severe reaction are not always enacted, implemented, or enforced. For example, epinephrine may not be available in relevant places, such as early care and education centers, schools, afterschool programs, camps, or airplanes. To promote greater safety in such settings, nongovernmental organizations are creating tools and guidelines to increase awareness, help parents and children with strategies for avoiding allergens, advocate for better policies, and/or increase the effectiveness of research efforts. Likewise, professional organizations of various industry sectors (e.g., manufacturers, retailers, food service) have created guidelines and training programs for their stakeholders. Federal, state, and local governments also are beginning to include allergy management as an element of their food safety policies. However, despite all the policies and guidelines for the various settings (e.g., food industry practices, regulatory agencies, early care and education centers, schools, higher education, and public transport), their development may not be keeping pace with the science and their implementation and enforcement varies greatly across the United States.

In addition, food allergy is a major global challenge and prevention strategies are needed across the globe. Although the prevalence and implementation of policies will vary by country, similar management approaches could be adopted across countries.

For all of these reasons, it was thought to be timely and important, in the interest of public health, for the National Academies of Sciences, Engineering, and Medicine to conduct a consensus study to review the science and management practices of food allergy. The committee intends that this report will (1) clarify the nature of the disease, its causes, and its current management, (2) highlight gaps in knowledge, (3) encourage the implementation of management tools at many levels and among many stakeholders,

and (4) delineate a roadmap to safety for those who have, or are at risk of developing, food allergy, as well as for others in society who are responsible for public health.

STATEMENT OF TASK

This study originated as a result of the broad public interest in the health aspects of food allergy; the relevance to public health, health care, and society; and the current lack of solutions both for the prevention of food allergy and its management. The apparent increase in food allergies, and concerns about a lack of good management strategies, prompted informal discussions that resulted in a planning meeting in Washington, DC, under the auspices of the National Academies of Sciences, Engineering, and Medicine on May 24, 2014. Various experts gave presentations on what is known about food allergy prevalence, causes, and risk determinants; perceptions regarding food labeling; and treatment approaches. Representatives from stakeholder groups with an interest in food allergy also attended. The group discussed the concerns related to those topics and provided comments about questions that would be of value to include in a consensus study from the National Academies. Following this meeting, a Statement of Task (see Box 1-2) was developed with contributions from all stakeholders.

APPROACH OF THE COMMITTEE

Expert Committee and Advisory Panel

An ad hoc committee of 15 experts was selected and nominated to respond to the statement of task. Committee members were drawn from a broad range of disciplines, including food allergens and methods of detection, pediatrics, clinical medicine, immune-related illness, genetics, epigenetics, the microbiome, epidemiology, biostatistics, nutrition/dietetics, food safety, public education, public health policy, clinical trials, prediction and prevention of food allergy, and child development. To expand the geographical context and experiences, food allergy experts from the United Kingdom and Australia were included in the committee. The committee held one public session on June 22, 2015, and one public workshop on August 31-September 1, 2015, to gather information. The committee also met on five occasions in closed sessions to discuss the findings, draw conclusions, and craft recommendations. The public session and workshop were valuable in providing the committee with the perspectives of sponsoring organizations and with information regarding diverse aspects related to the task (see Appendix A for public sessions and workshop agenda).

In order for the committee to consider the perspectives of those affected

by food allergy, the study also included an advisory panel made up of nine parents of children with food allergies and one individual with food allergy. The advisory panel members were selected from a group of approximately 50 individuals recommended by the sponsor organizations. All members of the advisory panel live with the challenges of food allergy on a daily basis and some are active advocates in their communities, participants in policy work and public speaking, or mentors for families who are new to food allergy. Although their opinions may not represent those of all people with the disease, they were invaluable to the committee as good examples of the sentiments and burden of living with food allergy. Some of the concerns brought up by this panel included the need for more clarity in food labeling, appropriate training for emergency personnel, access to epinephrine, and for improvements in well-being and safety at specific settings, such as schools, camps, restaurants, and transportation.

Boundaries and Clarifications About the Task

As mentioned above, food allergy, as a chronic disease, shares characteristics with other conditions and diseases. It is therefore necessary to be very clear about the task and its interpretation by the committee. The committee focused its efforts on the questions in the statement of task as they refer to the definition of food allergy by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). This definition states that food allergy is “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.” Food allergies fall into two major types—immunoglobulin E (IgE)-mediated and non-IgE-mediated—and the committee focused mostly on IgE-mediated food allergies (see Chapter 2 for definitions). Some of the discussions, where appropriate, also pertained to non-IgE-mediated food allergies, such as food protein–induced enterocolitis, particularly when discussing diagnostic methodologies that are unique for each type of food allergy. However, the literature reviews, findings, conclusions, and recommendations reviewed in this consensus study refer exclusively to IgE-mediated food allergies. Other food-related diseases, such as celiac disease, or food intolerances, such as lactose intolerance, or toxicity of food additives, are not covered in this report because they were beyond the scope of the statement of task.

Although any protein can be allergenic, certain proteins and specific foods that contain them (e.g., Ara h 2 in peanut) are characteristically allergenic and have been recognized as such because of the frequency or severity of the symptoms they cause in individuals at risk. The list of common allergenic foods varies by country. This variation is often due to the nature of diets or native foods in a given region but also to different criteria that are used

to qualify a food for inclusion in the list. The committee’s literature reviews were conducted from the perspective of foods that are considered allergenic in the United States. However, global evidence was considered to the extent that it informed the central issues the committee reviewed. Moreover, most recommendations also apply to any allergenic food today or those that may become clinically important allergens in the future. The committee did not review the scientific or regulatory aspects of the potential for proteins from genetically modified foods to be allergenic. The reader is referred to the 2016 National Academies of Sciences, Engineering, and Medicine report Genetically Engineered Crops: Experiences and Prospects for a review and recommendations on this topic (NASEM, 2016).

Although the study is meant to have a global perspective, it would not be feasible to answer all the questions in the statement of task from the perspective of all countries. Research data are being generated worldwide but implementation of research findings depends on contextual factors that would be different for each country or region. When it was valuable and feasible to do so, data collected about implementation in the United States, as well as in other countries, were used to guide the committee’s deliberations and recommendations. It should be noted that while the recommendations are focused on the United States, many could be implemented in other regions of the world.

This report is not meant to duplicate or replace important guidelines that have been developed in the past and that will continue to provide essential information about progress in diagnosis, treatment, and management of food allergy in the United States. Instead, this report is meant to be a call for unified action among all stakeholders and the public, both to recognize the importance of this disease and to join forces in efforts to markedly improve our ability to understand, effectively manage, and ultimately, cure this disease, and to make the world safer for those afflicted with it. Rather than conducting evidence-based reviews for all topics relevant to the task, the committee offered the support of specific guidelines where appropriate. In addition, the committee has conducted selected evidence-based reviews of the scientific literature where recent developments or the need for reinforcement deemed it necessary. Moreover, the committee did not review therapeutic approaches that are currently being investigated and instead recommended more research efforts in this area. These key guidelines include the following: 2010 NIAID/NIH-sponsored Guidelines for the Diagnosis and Management of Food Allergy in the United States: Report of the NIAID-Sponsored Expert Panel (Boyce et al., 2010), the European Academy of Allergy & Clinical Immunology (EAACI) Food Allergy and Anaphylaxis Guidelines (Muraro et al., 2014), two Practice Parameters (Lieberman et al., 2015; Sampson et al., 2014), and two Clinical Reports (Sicherer et al., 2007, 2010). Table 1-1 includes the guidelines (and system-

TABLE 1-1 Food Allergy Guidelines and Systematic Reviews

atic reviews on which they were based) and the names by which they are referred to in this report.

Gathering the Evidence

In addition to holding the public session and the information gathering workshop mentioned above and detailed in Appendix A, the committee used various approaches to respond to the questions in the statement of task. For example, it was possible to rely on the scientific literature to answer some of the questions. However, for questions related to current practices in the various settings encountered by those with food allergies, the committee relied more often on information gathered at workshops and/or by consulting the “gray literature” (published reports or research outside the traditional peer-reviewed scientific journals and commercial publications).

For example, to answer questions related to the prevalence of food allergy and the key prenatal and early life determinants of food allergies, evidence-based reviews were conducted as described in the report. To answer questions related to the definition, diagnosis, and prognosis of food allergy, as well as those related to managing food allergy in the health care setting, the committee did not conduct an extensive review of the literature because relevant recommendations have already been addressed in very recent authoritative reports. In such cases, primary resources for the findings, conclusions, and recommendations of the committee were derived from the 2010 NIAID/NIH-sponsored Guidelines (Boyce et al., 2010); the 2014 EAACI Guidelines and systematic review (de Silva et al., 2014; Dhami et al., 2014; Muraro et al., 2014), as well as the 2015 American Academy of Allergy, Asthma & Immunology (AAAAI) Guidelines (Lieberman et al., 2015), the 2014 AAAAI Practice Parameter (Sampson et al., 2014), and the two American Academy of Pediatrics (AAP) Clinical Reports (Sicherer et al., 2007, 2010). Additional searches in scientific databases were performed to identify specific items in the literature to supplement the discussion about specific topics, paying special attention to papers published after the aforementioned reports.

A DEVELOPMENTAL AND ECOLOGICAL PERSPECTIVE ON FOOD ALLERGY

During its review and deliberations, the committee recognized that addressing the task and goals of the consensus study would benefit from taking a developmental and ecological perspective. Preventing and treating food allergy, and delineating a roadmap to safety are a multifaceted undertaking that must take into account many interacting systems that

influence both risks and safety. For every individual, the risks and possible protections for food allergy vary and change over the life course, depending on individual genetic factors, biological development, exposures to allergens, and the nature of the contexts in which the individual lives. From a societal and public health perspective, the safety and well-being of many potential individuals with food allergy requires recognition that risks and protections for public safety are spread across many systems, including food production and distribution systems, health care systems, and education systems, among others. This section explains how the committee undertook a developmental and ecological approach toward the health and safety of individuals with food allergy.

Ecological Models of Individual Development

Ecological models of individual human development emphasize that the individual interacts with many social, cultural, and environmental systems throughout life and these interactions shape the development, health, and well-being of the individual over the life course (Boyce and Kobor, 2015; Bronfenbrenner and Morris, 2006; Gottlieb, 2007; IOM, 2005; Lickliter, 2013; Overton, 2013). These interactions span genetic to societal levels (Gottlieb, 2007; Lerner, 2006; Lickliter, 2013; Overton, 2013). The importance of taking a relational developmental systems approach to health promotion also has been applied by others (Halfon et al., 2014). From this perspective, the health and well-being of a developing individual is constantly changing as the individual interacts with the physical and biological environment, schools, family, and other contexts throughout life.

Proximal ecological systems (i.e., the social, cultural, and physical contexts) with which individuals interact directly over the life course have been termed “microsystems” in Bronfenbrenner’s bioecological model (Bronfenbrenner, 1979; Bronfenbrenner and Morris, 2006). In general, the health and well-being of individuals and populations with respect to food allergy are influenced by biological systems within individuals, including the microbiome, as well as human biological systems, and also their interactions with their physical contexts, including the built environment, plants, animals, microbiotic organisms, water quality, or climate, that could influence food allergy risk and/or protective processes.

Throughout the life course, however, the systems with which a person interacts vary. Before birth, a developing fetus interacts indirectly with systems in the broader context because the mother’s body is the entire proximal context and essentially all current extrinsic influences (e.g., diet or psychological trauma) are mediated by processes linking the fetus to the mother’s biological function. After birth, the caregiving system (i.e., parents and other caregivers) plays a primary role in mediating the experiences

of a baby, but now the child has additional direct experiences with other people and physical environments (e.g., health care, early care and education centers, and the social environments). As children continue to develop, they join and interact directly with numerous new systems, including peer groups, schools, and community services for children and families. Eventually, children begin to interact directly with social media, workplaces, and social and recreational contexts, such as sport teams, and religious or other cultural contexts.

Individuals also are influenced by many additional systems beyond their proximal interactions, through the influences of cultural practices and governmental or nongovernmental policies or rules that shape their contexts and experiences within societies and social groups. These relatively distal systems in the social ecology that influence individual development indirectly have been termed “macrosystems” (Bronfenbrenner, 1979; Bronfenbrenner and Morris, 2006). In the context of food allergy, for example, macrosystems include the laws and regulatory systems that affect food or the transportation industries and health care systems, religion, or mass media.

Human individuals adapt to the contexts of their development in multiple ways. An organism can adapt to a wider range of environments because developmental plasticity makes it possible for the developing phenotype to adjust to the environment in which it will live (Boyce and Kobor, 2015; Del Giudice et al., 2011; Hochberg et al., 2011; Szyf and Bick, 2013). For example, many of the adaptive systems that sustain health and well-being, including immune functions, stress responses, and language development, require some calibration for effectiveness within a given environment. It is conceivable that changes in modern life, including urbanization, mobility, and rapid environmental change, may have disrupted some processes of adaptive calibration, such that an individual could be “tuned” for one environment but live in or move to a radically different context. For example, exposure to microorganisms may trigger different responses depending on the timing. Growing up on a farm in a context of exposure to a rich assortment of microorganisms early in life may have protective influences on the risk for developing asthma. However, initial exposure to the same organisms later in life can trigger allergic responses (Figueiredo et al., 2013; Guerra and Martinez, 2008; von Mutius and Radon, 2008). The developmental timing of a person’s interactions with his or her context is an important consideration for understanding the origins and prevention of food allergy. Research is revealing that the timing of exposure to potential allergens can be a key determinant of whether or not food allergy develops in those at risk. The development and vulnerabilities to food allergy likely depend on an array of sensitivities to context that also may be shaped by the timing of exposures to potential allergens and other environmental fac-

tors. The committee considers these to be vital factors in promoting health and well-being for those at risk of developing food allergy.

From the perspective of an individual person or that person’s caregivers, a roadmap for safety in regard to food allergy must include a developmental understanding of current individual vulnerabilities and risks, informed by individual history, plus a detailed analysis of the risks and protective factors embedded in the contexts in which that person lives. A parent or caregiver actively protects a child with an allergy until that individual can manage on his or her own. As Box 1-1 illustrates, management of food allergy at the individual level can be challenging and complex. However, the task of a society to protect all its members with food allergy is even more complicated.

Complex Adaptive Systems in the Prevention, Treatment, and Management of Food Allergy

Health care and public safety systems have been described as examples of complex adaptive systems (Hammond, 2009; IOM and NRC, 2015; Lipsitz, 2012; Reiman et al., 2015). A complex adaptive system is composed of many heterogeneous elements whose interactions drive the system in ways that cannot be easily understood from considering only the separate elements. The elements can be social, physical, or biological. Specific properties characterize a complex adaptive system: individuality and adaptation, feedback and interdependence, heterogeneity, spatial complexity, and dynamic complexity (IOM and NRC, 2015).

Considering public risk, adaptation, and safety in relation to food allergy, examples of complex adaptive system features include the independent behavior of many individuals or their parents acting to avoid allergen exposure in the diet of self or child (adaptation and independence); the diverse responses of individual consumers to labels about allergens in food and to the experience of severe reactions to specific foods (independence, adaptation, heterogeneity); the actions of many independent businesses to customer concerns about allergies (independence, adaptation, heterogeneity, feedback) or to implementation of new state and federal regulations governing food production or sales (adaptation); the variation in sensitivity of individuals to the same potential allergen (adaptation, heterogeneity); the fact that different foods are considered allergenic in different countries (spatial complexity); and immunological changes during early development (dynamic complexity).

Efforts to change the safety of complex adaptive systems are complicated, whether the target of change is the entire public health care system, the commercial transportation systems, or the food production and service industries. Change is likely to require attention to issues of leverage,

resistance, cascading effects, and unanticipated consequences, as well as recognition that a single strategy is unlikely to change a large and multifaceted adaptive system. Changing one element in a complex system can have unanticipated consequences that raise problems in another part of the interconnected systems network. Moreover, it is difficult to move a complex system in the desired direction due to the complexity, heterogeneity, independence, and dynamic nature of its many component systems. Thus, solving problems in a complex adaptive system involves consideration of multiple levels and systems, multiple sectors, and multiple strategies. From this perspective, managing food allergy would include consideration of the roles of diverse actors, a multiplicity of processes, nonlinear and unexpected-emergent effects, counter-regulatory feedback loops, and many systems operating at different levels to achieve disparate goals. Examples of the many actors and settings (i.e., elements) that have a role in preventing and treating food allergy are individuals, families, schools, workplaces, food and transportation industries, and health care systems. As Reiman et al. (2015) stated, “Safety management of complex adaptive systems presents a great challenge” (p. 90). It may require appreciation of complexity in understanding and addressing the issues, distribution of adaptive capacity across levels, a balance of rules and flexibility, and an interactive process to steer the system toward greater safety.

ORGANIZATION OF THE REPORT

This introductory chapter describes how and why the study originated, the charge to the committee, and the developmental and ecological context. Chapter 2 is a background chapter that describes the definition of food allergy that the committee adopted, explains common food allergy signs and symptoms, summarizes common allergenic foods, and explains the mechanism of food allergy. It also comments on the misinformation among the many stakeholders in regard to what a food allergy is and how to prevent and manage it. Chapter 3 summarizes what is known about the prevalence of food allergy in the United States and abroad, highlighting the limitations in methods, especially in regard to prevalence trends. Chapter 4 includes the current diagnostic and prognostic methods used and others that are under investigation. Chapter 5 presents current knowledge about prenatal and early life determinants of food allergies, including genetic and environmental factors. Chapters 6, 7, and 8 contextualize the ways in which food allergy is currently managed in the health care system (Chapter 6), the food manufacturing industry (Chapter 7), and other settings such as schools and restaurants (Chapter 8). Chapter 9 includes all the committee’s recommendations for research. Finally, Chapter 10 culminates with the committee’s vision of a roadmap to safety, discussing how food allergy

can be prevented and managed based on evolving knowledge, taking into consideration the roles and responsibilities of the many actors and settings that an individual interacts with throughout the life course.

The committee envisions that this report will reach the many stakeholders, including the general consumer, patients, health care providers, school leaders, food manufacturers and establishment managers, and serve as guidance for future understanding and management of food allergies. The committee also has confidence that the recommendations in this report, if implemented, will stimulate progress in the understanding of food allergies, reduce further uptakes in prevalence, and improve the quality of life of those with this chronic disease and their caregivers.

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