9

Research Needs

This report represents the first review by the National Academies of Sciences, Engineering, and Medicine of the field of food allergy. The committee’s review identified a broad array of pressing questions that need to be addressed through new research in order to understand the scope and the underlying scientific mechanisms of food allergy; improve the management and treatment of food allergic children and adults and ultimately identify ways to prevent or cure food allergy; and inform policy and regulatory decisions concerning food production, labeling, and marketing. The implementation and vigorous pursuit of such a research agenda will constitute an important component of charting the “roadmap to safety” needed by the food allergic community (see Chapter 10). The following research questions were identified during the work of the committee and are organized to follow the report chapters, rather than according to priorities.

MECHANISMS OF FOOD ALLERGY (CHAPTER 2)

Conducting research related to the mechanistic processes underlying food allergy is essential in making significant advances to develop better methods to prevent disease or reduce its severity; predict, diagnose, and monitor disease; and optimally manage and treat, and ultimately to cure, food allergy. These mechanistic processes include disease predispositions, origins and onset, normal and disordered oral tolerance to foods, factors that contribute to disease severity, and variation in individual responses to different forms of therapy. In exploring mechanisms of action, including mechanisms of food allergy etiology, the committee recognizes the value

of animal models. However, a discussion of the benefits and limitations of using animal models is beyond the scope of this report. The readers are referred to some excellent reviews on the topic (e.g., Bogh et al., 2016; Van Gramberg et al., 2013).

One of the most prominent hypotheses for how food allergy develops—the dual-allergen hypothesis—proposes that environmental exposure to food allergens through the skin early in life can lead to allergy, while consumption of these foods during a developmentally appropriate period early in life results in tolerance. Under this hypothesis, children who avoid allergens in their diet but are still exposed to them in the environment might be more likely to develop an allergy than those not exposed. Supporting this hypothesis are data suggesting that early dietary introduction of peanut products may confer protection against peanut allergy as well as data suggesting that loss of function of filaggrin, a protein important for epithelial structure, confers a risk for food sensitization. However, many questions remain about the mechanisms by which sensitization and tolerance occur and about which elements of the immune system represent the most important contributors to the severity of food allergy or the establishment of tolerance (see Chapter 5). For example, studies have shown that biochemical indicators of tolerance include a reduction in allergen-specific immunoglobulin E (IgE) production, decreased allergen-IgE-induced basophil activation, increased allergen-specific IgG4, and induction of T regulatory (Treg) cells or anergic T cells. However, some of the data are conflicting and more studies are needed to better understand the role of these factors in food allergy.

During the perinatal period, interactions between the developing microbiota and the immune system at the cellular and molecular levels are likely influenced by environmental factors that can, in turn, influence health outcomes. Although the potential relationships between exposure to microbes early in life and the onset of food allergies have been explored, specific changes in the microbial profile of individuals, their particular interactions with the immune system, and how these interactions might be associated with food allergy have not been studied in depth.

To fill gaps in knowledge in this area, studies should be conducted to accomplish the following objectives:

• Elucidate the molecular and cellular mechanisms that account for the differences between innate tolerance versus food sensitization and between food sensitization versus food allergy.
• Identify the mechanisms, in patients with food allergies, for acquiring tolerance to the offending food allergen, without therapeutic intervention, as well as for responding to therapeutic interventions

• by developing transient desensitization versus sustained unresponsiveness versus true tolerance to the offending food allergens.

• Define how particular products and functions of mast cells, basophils, and other effector cells can contribute to the signs and symptoms of food allergic reactions, including anaphylaxis, and identify factors that may contribute to individual variation in the pathophysiological responses to such products.
• Study the role of immunoglobulins other than IgE, such as IgG4 or IgA, and of effector cells in addition to mast cells and basophils, in modulating (i.e., enhancing or reducing) food allergic responses.
• Identify and describe the roles of the skin and intestinal barriers in protecting individuals from developing food sensitization or a food allergy, and identify ways in which protective aspects of barrier function can be enhanced and factors that diminish barrier function be reduced.
• Examine the interactions between the microbiota and the host immune system that may favor or protect against the development of a food allergy, and define the extent to which the microbiota or its products can be manipulated to enhance resistance to the development of food allergy.

PREVALENCE AND COST OF FOOD ALLERGIES (CHAPTER 3)

One of the committee’s recommendations is to perform well-designed and adequately powered studies to estimate the true prevalence of food allergy (see Chapter 3). In addition, the committee concluded that better methods to collect information about anaphylaxis reactions are needed. Estimates of the various costs of food allergy are needed as well. For example, the Centers for Disease Control and Prevention has developed tools to estimate the costs associated with some chronic diseases, such as arthritis. Medical expenditures for managing food allergy place financial burdens on society, as well as on the individuals affected and their caregivers. Additional costs relate to quality of life, productivity in school or at work, and food recalls. Estimates on cost burden are necessary for prioritizing research and resources, and for effectively advocating for implementation of practices and policies that will reduce those costs. These estimates should include the costs to society, such as those related to health care and productivity losses due to absenteeism, the costs to families and patients in terms of lost quality of life, and costs to the food industry due to food recalls.

The following research needs are warranted to improve data on severe reactions and on cost estimates:

• Evaluate various methods of collecting national data on food allergy severe reactions such as by leveraging the existing surveillance systems (e.g., the National Health and Nutrition Examination Survey or the National Electronic Injury Surveillance System) or by developing a Web-based reporting system for anaphylaxis in the community.
• Collect and analyze data to estimate the economic and social costs of food allergy based on current prevalence of both mild and severe reactions and on objective measures of costs, such as data on medical expenses and time lost from school and work. Collect these data on different ethnicities and socioeconomic strata. The costs to industry due to food recalls and implementation of allergen control strategies also should be estimated.

RESEARCH ON DIAGNOSIS AND PROGNOSIS (CHAPTER 4)

Diagnosis of food allergy is complex, currently requiring expertise in assessing the medical history, understanding allergen cross-reactivity, understanding eliciting factors that may alter reactivity, selecting and interpreting imperfect tests, and possibly conducting a medically supervised oral food challenge (OFC) test. The OFC is currently the best diagnostic test to confirm an allergy, but it is time-consuming, expensive, carries risks (e.g., the risk of triggering an allergic reaction), and is often deferred due to patient and physician concerns. Therefore, the OFC is underused. In addition, commonly available simple allergy tests (serum-specific IgE antibody tests or skin prick tests [SPTs]) have limitations that can result in misdiagnosis, primarily overdiagnosis, requiring procedures such as OFCs to confirm a proper diagnosis. For example, currently available, simple diagnostic tests that are often used to diagnose IgE-mediated food allergies, the serum food-specific IgE test and the SPT, actually diagnose sensitization, not food allergy. A variety of diagnostic tests, such as component resolved diagnostics, the basophil activation test, and many others, are emerging or under study and may better inform diagnosis, prognosis, severity, and threshold.

To fill gaps in knowledge in this area, studies should be conducted to accomplish the following objectives:

• Optimize the currently available diagnostic tests and validate methods, such as OFC (including in special contexts, such as OFC in infants and young children), as well as pursue additional novel tests to improve diagnosis, prognosis, determination of severity of disease, and assessment of antigen thresholds, and to monitor host responses. These tests will be valuable in assessing the effectiveness and durability of interventions, such as immunotherapy. These

• studies should include all affected patient populations (ages, sexes, ethnicities, comorbidities, socioeconomic strata), should consider the role of eliciting factors (such as exercise and infections), and also should be assessed in those circumstances where interventions are being applied to the patient (immunotherapeutic strategies as they become available).

• Comprehensively examine the utility, cost-effectiveness of, and barriers to testing, especially regarding the OFC, with a goal of maximizing the use of appropriate tests.
• Examine and assess educational approaches and tools to improve physician and health care provider education about both the natural history of food allergies and the appropriate approaches to use to diagnose food allergies.
• Study the utility of emerging technologies in the area of “omics” methodologies (e.g., genomics, epigenomics, metabolomics). In particular, identify reliable and clinically useful biomarkers for the following important goals:
  • Assessing the severity of a food allergy (e.g., to identify those at high risk for anaphylaxis)
  • Evaluating and monitoring responses to therapy (e.g., immunotherapy)
  • Predicting prognosis (e.g., predicting severity)
  • Identifying populations at risk of developing a food allergy so that they can be included when conducting research on prevention and management strategies and on public health guidelines
  • Diagnosing food allergy in individuals and populations (e.g., for collecting data on prevalence)

RESEARCH ON RISK DETERMINANTS AND PREVENTION (CHAPTER 5)

Considerations for Study Designs

Studies on the etiological factors associated with food allergies frequently present methodological flaws due to various reasons, including lack of accounting for confounding factors (e.g., breastfeeding), use of inaccurate food allergy measures (e.g., self-reporting), or disregard for the fact that different populations (e.g., those at high risk of developing a food allergy) might respond differently to the various risk factors. For example, due to a variety of differential gene-environment factors (e.g., genetics, epigenetics, microbiomes, and other pre- and postnatal environmental factors), populations will respond differently to interventions. Also, the etiology

and early life onset of food allergy seems to be multifactorial, and collecting specimen for future analyses would be advantageous. Future research design on etiological determinants should consider the following:

• Conduct longitudinal birth cohort studies that explore the effects of environmental factors during critical developmental windows (in utero, infancy, and early childhood) on food allergy.
• Couple relevant prenatal, perinatal, and early childhood epidemiological and clinical data with appropriate biospecimen collections (e.g., serum, cord blood, breast milk) for current and future bio-marker analyses.
• Design studies so that the responses to various exposures of individuals and populations at high risk and low risk of developing food allergy can be differentiated.
• Use the currently accepted gold standard—double-blind, placebo-controlled OFCs (employing standard dosing protocols and scoring systems, so that the results of various studies can better be compared)—as the food allergy outcome in research intervention studies until a simpler reliable method to measure food allergy is identified and validated.
• Account for the potential influence of confounding factors, in addition to age, sex, and geography, such as breastfeeding, composition of breast milk, dietary intake, other allergic disorders in the patient or family history (particularly atopic dermatitis), genetic susceptibility, presence of dogs or cats in the household, number of siblings, history of antibiotic usage, and exposure to agents or practices that might impair skin barrier function.
• Engage patients or groups representing patients so that research designs may take into consideration potential socio-psychological, cultural, and behavioral considerations.

Overall Research Needs

Many genetic and environmental factors could contribute to the onset of sensitization and to food allergy. For the majority of factors reviewed by the committee, some, but largely insufficient or inconsistent, evidence exists at this time about their association with sensitization or food allergy. Nevertheless, health care providers, patients, and their caregivers still need clear prevention approaches and authoritative and clear public health guidelines. Therefore, research needs to continue to support or refute the contribution of these factors to food sensitization or food allergy. The committee recognizes, though, that for other factors direct or indirect evidence is lacking and research is not currently warranted (e.g., food additives). Although

some public health guidelines have been developed to guide practices of health care providers and individuals, efforts have not been undertaken to assess the impact of such public health guidelines on practices related to food allergy and on prevalence of food allergy. Prospective studies and behavioral research should be conducted to accomplish the following objectives:

• Examine risk factors for food allergies in all populations (ages, sexes, ethnicities, comorbidities, socioeconomic strata), especially in those populations that might have been underrepresented in past research.
• Gain insights about the behaviors of those with (or at risk of) food allergy and their caregivers as well as about the impact of public health guidelines on health care providers and individuals’ practices.
• Examine the etiology of the rising prevalence of food allergy within the past two decades, which could identify new targets for allergy prevention and treatment. For example, what changes have occurred in food preparation and consumption behavior in communities and what is their potential relationship to the increase in food allergies? What changes may have occurred in the use of agents (such as detergents) or practices (such as in personal hygiene) that might contribute to impaired skin barrier function?
• Elucidate, through prospective studies, the role of environmental factors and gene-environment interactions in the atopic march and the development of food allergy. For example, do specific factors increase the risk of an individual progressing from eczema to food allergy?
• Explore potentially unidentified risk factors that may influence food allergy. For example, although the data available to date have not shown evidence of a relationship, it is plausible that maternal and early childhood adiposity and metabolic disorders could be risk factors for food allergy development.
• Using prospective birth cohort studies, evaluate the effects of multiple early life factors (individually and in combination) and of possible gene-environmental interactions in the development and prevention of food allergy in order to inform the design of specific randomized controlled trials (RCTs).
• Identify the best practices to engage patients and their families in the planning stages of research studies so that patients’ and families’ concerns are considered, and assess the value of using these approaches.

Specific Research Needs

In addition, high-quality prospective studies and RCTs are needed on specific risk determinants for which some evidence exists about their effect on food allergy related to the most plausible hypotheses to make meaningful conclusions. These studies should be conducted to accomplish the following objectives:

The Microbial Hypothesis

• Determine, using well-designed prospective studies, the role of mode of birth delivery (vaginal, emergency versus elective cesarean section) and early life microbiome composition on the development of food allergy.
• Assess, through well-designed prospective studies, potential links between food allergy and antibiotic exposure in children (studies should include information on the type, dose, and frequency of antibiotic exposure).
• Determine whether pet ownership is related to food allergy by using well-designed prospective studies.
• Assess, with RCTs, the potential benefits of prebiotics and probiotics to prevent the onset of food allergy.

Allergen Avoidance and Exposure

• Elucidate the relationship, if any, between breastfeeding and the onset of food allergy (may also influence through microbiome modulation) with well-designed prospective studies and take into account the potential effect of differences in breast milk composition.
• Determine, with RCTs, whether consuming or eliminating or avoiding specific allergenic foods during pregnancy and lactation has any benefits.
• Conduct RCTs, similar to the Learning Early About Peanut study, to determine whether early introduction of peanut products has benefit in individuals other than high-risk infants, who were studied in the original trial.
• Examine early introduction of allergenic foods in addition to peanut to determine whether this approach is beneficial in preventing the development of food allergy.

Nutrition Immunomodulation Hypothesis

• Assess, with RCTs, the potential role of specific nutrients, such as vitamin D, folate, or fatty acids, in preventing food allergy.

RESEARCH ON HEALTH CARE SETTINGS AND OTHER SETTINGS (CHAPTERS 6, 7, AND 8)

Health Care Settings

Food allergy management primarily requires avoiding the trigger allergen(s), but this approach requires extreme care; knowledge of cross-contact, hidden ingredients, and the effect of processing; and knowledge of ingredients through label reading and other methods. It is prone to accidents resulting in allergic reactions. Numerous obstacles arise for food-allergic consumers attempting to obtain safe meals outside the home. Surveys among individuals with food allergy, caregivers, and health care providers reveal deficiencies in food allergy knowledge and concerns about accidents, especially among adolescents and young adults. Only limited programs are available for educating individuals, caregivers, and health care providers on strategies to obtain and provide safe meals outside the home, with few validated programs and limited information on implementation. In addition, validated, evidence-based dietary guidance is lacking for those avoiding allergens, such as milk or multiple foods. Knowledge about potential interventions that health professionals could use to improve individual psychosocial status, such as to improve quality of life or alleviate anxiety, also is lacking.

In regard to management, some areas of research need further study. For example, no means are currently available to reliably predict severity of anaphylaxis, which would be valuable for health care providers, individuals with food allergy, and their caregivers. In terms of managing anaphylaxis, underuse of epinephrine, the primary treatment for anaphylaxis, is common but the reasons are unknown. In addition, the fixed doses of epinephrine in auto-injectors may not be appropriate for infants or for individuals with obesity. Also, medications used as primary and adjunctive therapy for anaphylaxis (e.g., epinephrine dosing, bronchodilators, antihistamines, corticosteroids) have not been studied. Standardized emergency plans for individuals that can be used by caregivers at home or school also do not exist.

To address those gaps in knowledge, the following research areas should be pursued on all affected populations (ages, sexes, ethnicities, comorbidities, socioeconomic strata), especially on underrepresented populations:

• Determine the effectiveness of evidence-based guidelines and evidence-based educational programs on food allergy management, including avoidance of allergens and emergency management of allergic reactions and anaphylaxis, for health care providers and for patients, particularly for high-risk groups.
• Assess the following management issues:
  • The effectiveness of approaches other than strict allergen avoidance
  • The role of food allergy in other chronic allergic conditions
  • The identification of means to recognize clinically relevant versus nonrelevant allergen cross-reactivity
• Identify risk factors and biomarkers of food-induced anaphylaxis, particularly to identify individuals at high risk of severe reactions.
• Assess the safety and efficacy of adjunctive therapies for anaphylaxis, especially bronchodilators, antihistamines, and corticosteroids.
• Devise safe and effective therapies for food allergy, including those that can induce long-term desensitization and tolerance (i.e., sustained remission), and ideally a true cure.
• Improve understanding of the nutritional needs of persons on food allergen avoidance diets, how best to determine their need for dietitian evaluation/management, and how to develop evidence-based medical nutrition therapy.
• Evaluate whether consulting with a dietitian or a mental health professional improves quality of life and understand barriers to referring patients to dietitians or mental health professionals.
• Explore the best means to identify and intervene about psychosocial concerns associated with managing food allergy.
• Identify best practices for providing a uniform written emergency action plan for anaphylaxis. Consider using the recent American Academy of Pediatrics guidelines as the reference for a best practice study.
• Determine the proper dose of epinephrine in infants less than 10 kg and in individuals with obesity.
• Characterize risks associated with nonoral allergen exposures (e.g., skin-exposure and inhalation).

Risk Assessment and Factors Affecting Allergic Reactions to Foods

Some allergenic foods have higher potency and cause more severe reactions than do others. Likewise, evidence indicates that changes in proteins during food processing can contribute to their allergenicity, but these changes and their effects are not the same for all allergenic proteins. The relationship between specific protein characteristics (e.g., structure, sensitiv-

ity to heat, and digestibility) and specific processing conditions and potency needs to be elucidated so it can be considered when designing research studies and when prescribing prevention approaches for individuals.

In addition to age and geographical differences, circumstantial factors might modify the severity of a food allergy reaction and the level of allergen needed for a reaction in an individual. The effect of exercise on experiencing a food allergy reaction has been reported and it is well recognized. However, for other factors, such as alcohol or medication use, biological cycles, psychological factors, stress, and concomitant allergen exposures, anecdotes are the main source of information. Identifying the factors that can modify the severity of allergic reactions and defining their influence on whether an allergic reaction is experienced upon exposure to a food allergen or in changing the specific eliciting dose are key pieces of information needed to provide advice to individual patients (see Chapters 6 and 7).

To fill gaps in knowledge in this area, studies should be conducted to accomplish the following objectives:

• Strengthen current knowledge about: food allergen risk assessment and management, including continued assessment of threshold doses for individual allergens; single dose oral challenges for confirmation of threshold doses; the development, application, and improvement of parametric dose-distribution modeling approaches for allergen risk assessment; food consumption patterns of food-allergic populations; and improved methods for detecting allergen residues in food matrices.
• Study the mechanisms that make some food proteins more allergenic than others and the effects of food processing methods and other ingredients on their allergenicity and thresholds.
• Study the possible effects of augmentation factors on threshold doses (e.g., exercise, alcohol) or on modifying the severity of reactions, and the mechanisms underlying such effects.

Managing Food Allergies in Food Establishments, Food Service, Schools, and When Traveling

Allergic reactions occur among children attending early care and education settings, schools, camps, or college, as well as among children and adults while traveling or eating at a food establishment and may include persons without a prior diagnosis. Although anecdotal reports describe severe reactions, well-documented estimates of such reactions in each setting are not available. Also, although federal and local policies exist, such as the Food and Drug Administration (FDA) Food Code, no studies have been conducted on the extent to which regulatory policies have been imple-

mented and the impact of those policies on management or prevalence of food allergy.

The obstacles for consumers with food allergy in restaurants, food establishments, and during travel include lack of communication between the consumer and staff and lack of knowledge about ensuring safety for consumers with food allergies. Limited programs exist for education and more studies are needed to create and validate food allergy educational materials and programs.

Best practices for managing food allergies in settings of concern where food is served have not been studied. For example, management plans for food allergy in early care and education settings, schools, camps, or other places where children are served food include providing instructions for safe meals, recognizing and managing reactions, and assigning roles and responsibilities. These plans require different strategies according to age of the child, skill level of the supervising adults, and cultural or socioeconomic context, but these factors have not been extensively studied and a paucity of data exist upon which to base best practices.

To fill gaps in knowledge in this area, studies should be conducted to accomplish the following objectives:

• Monitor the number of food allergic reactions that occur in various settings where food is served, particularly in early care and education settings, schools, camps, and food establishments, and in additional settings of concern, including restaurants, cafeterias, grocery stores, and commercial airliners (or other commercial means of travel).
• Monitor the degree to which states adhere to the FDA Food Code and other laws and regulations with a food allergy component (e.g., the number of children with individualized education programs¹ due to food allergy) so that best practices are developed and their effectiveness in the prevention of severe reactions and management of food allergies is evaluated.
• Define best practices regarding food allergy management (e.g., epinephrine storage) at settings where food is served, particularly in early care and education settings, schools, camps, and food establishments in additional settings of concern, including restaurants, cafeterias, grocery stores, and commercial airliners (or other

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¹ In public schools, students with a disability may qualify for Individualized Education Program, under federal special education funding through the Individuals with Disabilities Education Act (IDEA) of 1975, and may receive special education and related services. See more at: http://www.foodallergyawareness.org/civil-rights-advocacy/schools-2/individualized_education_program_(iep)-2/#sthash.F4dKKnbV.dpuf (accessed January 6, 2017).

• commercial means of travel). The experiences of other countries where management practices have been standardized should be considered.

• Develop and implement evidence-based, effective training programs for relevant personnel at settings where food is served particularly in early care and education settings, schools, camps, and food establishments in additional settings of concern, including restaurants, cafeterias, grocery stores, and commercial airliners (or other commercial means of travel). The experiences of other countries where effective training programs have been standardized should be considered.
• Identify and explain risks associated with environmental exposures to food allergens through skin contact or inhalation.

REFERENCES

Bogh, K. L., J. van Bilsen, R. Glogowski, I. Lopez-Exposito, G. Bouchaud, C. Blanchard, M. Bodinier, J. Smit, R. Pieters, S. Bastiaan-Net, N. de Wit, E. Untersmayr, K. Adel-Patient, L. Knippels, M. M. Epstein, M. Noti, U. C. Nygaard, I. Kimber, K. Verhoeckx, and L. O’Mahony. 2016. Current challenges facing the assessment of the allergenic capacity of food allergens in animal models. Clin Transl Allergy 6:21.

Van Gramberg, J. L., M. J. de Veer, R. E. O’Hehir, E. N. Meeusen, and R. J. Bischof. 2013. Use of animal models to investigate major allergens associated with food allergy. J Allergy (Cairo) 2013:635695.

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