6

Management in the Health Care Setting

Proper management in the health care setting begins with an appropriate diagnosis of food allergy so that the patient can be instructed on specifically which foods can trigger allergic symptoms. Once a diagnosis is established, management relies on educating the patient and family on avoiding the allergen and preparing to treat allergic symptoms, including severe allergic reactions (i.e., anaphylaxis) promptly and appropriately. Additionally, daily management of food allergy carries potential nutritional, social, and emotional ramifications that should be addressed. Achieving these goals requires significant patient and family education and counseling. Emerging approaches for treatment show promise for altering the threshold of reactivity, making exposure to small amounts of the food less problematic, and future treatments will ideally result in elimination of the allergy.

This chapter covers management of diagnosed food allergy from the perspective of a health care setting and includes topics such as the impact of food allergy on affected individuals and families and the current understanding of food allergy treatment. Dietary issues with regard to prevention are discussed in Chapter 5. This chapter also highlights the importance of educating health care providers about food allergy and management advice for the home, public environments, and high-risk scenarios. From a developmental and ecological perspective, the instructions provided at the health care setting represents only one aspect of successful management because successful adherence depends on management and sensitivity toward food allergy from all societal sectors, including families, schools, food service, and the community. Chapter 7 focuses on management of food allergies in

other settings such as schools, restaurants, and travel, and on the safety of manufactured products.

APPROACH TO LITERATURE REVIEW

The topics addressed in this chapter did not undergo individual systematic review or meta-analysis. The primary resources for discussion, findings, conclusions, and recommendations were derived from various guidelines (see Chapter 1, Table 1-1, for a description of the guidelines): the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH)-supported Guidelines (Boyce et al., 2010) and its associated literature reviews, the European Academy of Allergy & Clinical Immunology (EEACI) Guidelines (Muraro et al., 2014a,b) and associated systematic reviews (de Silva et al., 2014; Dhami et al., 2014), the American Academy of Allergy, Asthma & Immunology (AAAAI) Guidelines (Sampson et al., 2014); the AAAAI Practice parameter (Lieberman et al., 2015), and American Academy of Pediatrics (AAP) Clinical Reports (Sicherer et al., 2007, 2010). Additional PubMed searches were performed to identify items in the literature to supplement the discussion on specific topics, especially for papers published after the aforementioned reports. Meta-analyses and systematic reviews were selected when available.

ALLERGEN AVOIDANCE AND RECOGNITION OF AND PREPAREDNESS TO TREAT ALLERGIC REACTIONS AND ANAPHYLAXIS

General Principles of Management, Avoidance, Cross-Contact, Hidden Ingredients, Routes of Exposure

The primary advice for managing a diagnosed food allergy, whether immunoglobulin E (IgE)-mediated or non-IgE-mediated, is to avoid ingesting the culprit food allergen(s) (Boyce et al., 2010; Muraro et al., 2014b; Sampson et al., 2014). Of course, no randomized clinical trials (RCTs) have been conducted to evaluate this approach, but not ingesting the allergen is a rational management strategy for a diagnosed food allergy. No evidence exists that avoidance affects the natural course of atopic dermatitis, asthma, or eosinophilic esophagitis (Allen et al., 2009; Boyce et al., 2010). Maternal avoidance of a food allergen may be needed in some cases if the infant, diagnosed with a food allergy, experiences reactions from the maternally-ingested allergen while breastfeeding (Jarvinen et al., 1999; Lifschitz et al., 1988; Monti et al., 2006).

Achieving avoidance of a food allergen entails numerous considerations involved in obtaining or preparing allergen-safe foods. For example, cross-

contact is a term describing a situation where an unintended allergen may be present in an otherwise allergen-free food because of contact between the unsafe and safe food. Examples of cross-contact include having a knife used in peanut butter placed into a jar of jelly, using a fryer with oil exposed to fish and egg ingredients used for potatoes, and placing a spoon used to stir a milk-containing soup into a milk-free one.

The possibility of hidden ingredients is also a concern (see also Chapter 7). For example, an individual with food allergy may not have expected that chili or spaghetti sauce may contain peanut flour, that peanut butter may be used to seal the ends of an egg roll, or that “non-dairy” creamers contain casein, the major allergenic protein in cow milk.

Avoiding ingestion of a food allergen requires patient education about obtaining safe foods in numerous settings, for example reading labels on packaged foods,¹ asking before ordering in restaurants and food service, and preparing safe meals at home. Standard cleaning procedures, such as using wet wipes and washing hands with running water and soap, typically suffice to remove allergen from surfaces. However, topical antibacterial hand cleaning agents do not neutralize allergens (Perry et al., 2004). Ingestion contact with an allergen occurs from sharing utensils or straws or from intimate kissing where saliva containing the allergen may transfer to the allergic individual (Eriksson et al., 2003; Hallett et al., 2002; Maloney et al., 2006). Young children may need supervision when around food allergens to avoid taking or being fed the allergen, or having hand-to-mouth transfer of food allergens.

The primary route of exposure that triggers serious reactions—for example, severe anaphylaxis or fatal reactions—is through ingestion (Fleischer et al., 2012; Sampson et al., 2014). Modest allergen contact with intact skin is unlikely to trigger serious reactions (Simonte et al., 2003; Wainstein et al., 2007), but transfer from hand to the mouth can be a concern, and the eyelid may swell significantly with direct contact. Aerosolizing² food proteins (e.g., from boiling milk, frying egg or fish, cooking with wheat flours) may trigger reactions, often respiratory symptoms, depending on proximity, amount aerosolized, and patient-specific factors, such as asthma and degree of sensitivity (Roberts et al., 2002). Aerosol exposure can be a concern in occupational settings (e.g., “baker’s asthma”). Peanut butter, an oily substance, does not aerosolize enough to trigger reactions (Simonte et al., 2003).

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¹ The section on packaged foods below describes the current regulatory frameworks for food labeling of packaged foods that attempt to inform consumers of the presence of an allergen in a food.

² Aerosolizing is the process or act of converting some physical substance into the form of particles small and light enough to be carried on the air.

The complexities of avoidance management requires a proper diagnosis followed by a comprehensive approach to educating patients, families, caregivers, and others on appropriate measures. Mistakes and subsequent allergic reactions are common. A prospective study of 512 infants with food allergy followed for a median of 36 months noted 1,171 reactions among 367 children (Fleischer et al., 2012). Common reasons for reactions included accidental exposure, label reading errors, and cross-contact, but the study also noted some exposures were purposeful, suggesting they were done presumably to test whether the allergy was active. Additionally, the source of ingested foods during accidental exposure included siblings, relatives, and other caregivers. This study reflects the many potential sources of error in avoidance management and the need for comprehensive education. A 2015 systematic review regarding unexpected allergic reactions in those older than age 12 years (Versluis et al., 2015) identified 18 observational and 6 qualitative studies. The authors noted that current knowledge about the frequency of unexpected reactions is limited, that reactions can be severe and fatal, and that most reactions were noted to have taken place at home though other locations, such as restaurants and others’ homes, were common. They also identified various labeling issues and risky behaviors as problems and concluded that patient education and dietary instruction are needed.

EDUCATING PATIENTS ABOUT ALLERGEN AVOIDANCE

This section presents several topics where health care providers should provide advice to their patients with food allergy. Many of the topics relate to allergen avoidance, the main advice given to patients. They include strictness of allergen avoidance, avoidance and comorbidities, and concerns about cross-reactive foods. These topics are covered to various degrees in Boyce et al. (2010); Muraro et al. (2014b); and Sampson et al. (2014). The topic of nonstrict avoidance is discussed in more detail in the review by Kim and Sicherer (2010).

Strictness of Allergen Avoidance

Typically persons with a food allergy are advised to strictly avoid the trigger food (Boyce et al., 2010; Kim and Sicherer, 2010; Muraro et al., 2014b; Sampson et al., 2014). However, individuals with a mild allergy, particularly allergies related to pollen-food allergy syndrome, may not need to strictly avoid the trigger fruit or vegetable. Similarly, those with food-associated, exercise-induced anaphylaxis may only need to avoid the identified trigger only in the hours before exercise. A majority of children with cow milk or egg allergy are able to ingest extensively heated forms of these

foods, for example when baked into a muffin. Additionally, circumstantial evidence from observational studies suggests that ingesting these forms does not impede recovery from these allergies and may speed tolerance induction (Kim et al., 2011; Leonard et al., 2012; Nowak-Wegrzyn et al., 2008; Tey et al., 2012). For individuals with a high threshold of reactivity, allowing ingestion of sub-threshold amounts of the allergen has not been studied. Limited evidence from a study of young children suggests that an isolated exposure to egg, milk, or peanut resulting in an allergic reaction does not increase allergen-specific IgE responses (Sicherer et al., 2016). More studies are needed to understand circumstances where nonstrict avoidance would suffice. In some situations, nonstrict avoidance is an option that can be considered under medical guidance. For example, as presented in Chapter 7, this committee recommends the implementation of a risk-based approach for labeling foods with unintended allergens which, under medical consultation, should improve the ability of individuals with food allergy to decide whether they can safely consume a specific packaged food.

Allergen Avoidance and Relationship to Comorbid Asthma, Atopic Dermatitis, and Allergic Rhinitis

Food allergen avoidance is generally not recommended as a primary means to address treatment of asthma, atopic dermatitis, or allergic rhinitis. However, avoidance is warranted when a specific food allergy is diagnosed in a patient with those diagnoses (Boyce et al., 2010; Sampson et al., 2014). If a food allergy is diagnosed, limited evidence suggests that avoiding the allergen may improve atopic dermatitis (Agata et al., 1993; Bath-Hextall et al., 2009; Boyce et al., 2010; Lever et al., 1998). Studies have suggested that following extended elimination of a food that had not previously caused serious reactions, for example only flare of atopic dermatitis, re-exposure to the food could result in acute systemic allergic reactions (Chang et al., 2016; David, 1984; Flinterman et al., 2006). Although this observation raises caution, no RCTs have been performed to confirm this association.

Concerns About Cross-Reactive Foods

Food with proteins that are homologous³ to a food protein to which an individual is allergic may present a reaction risk (Boyce et al., 2010; Sampson et al., 2014). For example, an individual with a peanut allergy may be at higher risk for allergy to beans (e.g., soy) because both foods

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³ Homology between proteins is defined in terms of shared ancestry and is typically inferred from the similarity of their amino acid sequence.

are legumes. However, clinical cross-reactivity varies among families of foods and also among individuals depending upon their allergy profile. Unfortunately, testing has limited value because sensitization to foods with homologous proteins, evidenced by positive skin prick tests (SPTs) or the presence of food-specific IgE antibodies, is much more common than is clinical allergy (Boyce et al., 2010; Sampson et al., 2014; Sicherer, 2001) (see Chapter 4 for a detailed discussion of testing). Foods with high likelihood of clinically relevant cross-reactivity include milk from cows and goats; tree nuts, specifically cashew with pistachio and walnut with pecan; various fish with each other; and between crustacean shellfish, such as shrimp and lobster. In contrast, grains and legumes have less co-allergy. Decisions about avoiding related foods may rely also on factors such as concerns about accidental exposure from misidentification or cross contact. For example, an individual with food allergy who tolerates walnut but not cashew may decide to avoid all tree nuts to avoid cross-contact or misidentification. Therefore, advice about the need to avoid potentially cross-reactive foods is individualized and may require extensive testing with oral food challenges (OFCs). Adherence is, obviously, more difficult. Education of patients and families about these concerns is required for proper management.

ADVICE ON ALLERGEN AVOIDANCE IN VARIOUS SETTINGS OF CONCERN

Packaged Foods

Laws governing the labeling of allergens in packaged foods vary by country (Akiyama et al., 2011; Gendel, 2012) and are described in Chapter 7. Health care providers should discuss current labeling laws in counseling those who have a diagnosed food allergy. The current U.S. labeling law, the Food Allergen Labeling and Consumer Protection Act of 2004, requires manufacturers to use plain English terms to identify milk, egg, wheat, soy, peanut, tree nuts, fish, and crustacean shellfish ingredients. These may be included in the ingredient list and/or in a separate “contains” statement. Highly refined oils are exempt based on removal of protein by the process. The individual name of the food is required for categorical foods (e.g., walnut, cashew, shrimp, tuna, cod). Noncrustacean seafood, such as clam, oyster, scallop, is not included in the laws. Foods that are known to cause serious allergic reactions are not necessarily included on the label, for example, sesame and mustard (Caballero et al., 2002; Dalal et al., 2012) because they are not included in the U.S. list of priority allergens (see Chapter 7).

In the United States and some other countries, when manufacturers perceive the possibility of allergens being unintentionally included in the

product, they may voluntarily use precautionary or advisory terminology, such as “may contain X,” “in a facility with X,” and other such terms. Studies suggest varied risks with such products (Crotty and Taylor, 2010; Decastelli et al., 2012; Ford et al., 2010; Hefle et al., 2007; Robertson et al., 2013; Zurzolo et al., 2013) and consumers should be counseled that the terms do not reflect degree of risk. As Chapter 7 concludes, labeling laws help consumers to identify most, but not all, allergens, and advisory labeling has resulted in an unregulated proliferation of warnings that are not well understood by consumers or health care providers, and appears to result in risk-taking behavior. For example, findings from a recent survey administered in 16 countries suggest limited understanding among individuals with food allergy about food allergen thresholds (Marchisotto et al., 2016). In addition to managing the risks from packaged foods by replacing the current food allergen precautionary advisory labeling system, as recommended in Chapter 7, risks from consuming packaged foods should be communicated to individuals with food allergy and their caregivers by effective counseling in the health care setting.

Management at Home

Management of food allergen avoidance in the home requires constant vigilance regarding cross contact, label reading, and hidden ingredients. Typical cleaning methods should remove allergens from utensils, dishes, and surfaces. Depending on age and developmental ability, different safeguards may be needed to protect a child from ingesting the avoided allergen. For example, allergens may need to be kept out of reach of younger children who are not aware of the danger. Families may need to consider keeping the food-allergic individual away from the allergen during food preparation areas if aerosolization is likely (e.g., frying fish or eggs, boiling milk, steaming lobster, preparing food with wheat flours or powdered milk). Maintaining a continuous safe environment is challenging and time consuming. Health care providers should review these issues with patients and families.

Management in Food Service Settings and During Travel

People who are food allergic must navigate multiple issues when dining away from home, including avoiding cross-contact and hidden ingredients in foods served at food service establishments such as restaurants, ice cream parlors, bakeries, grocery stores with prepared foods, and food carts (see also Chapter 8). Informing the establishment about the allergy is the patient’s or family’s responsibility, but the establishment also must be able to take precautions to provide safe food to the public. Factors contributing

to risk could be the presence of allergens in the source ingredients or cross-contact with allergens at the buffets and food preparation areas.

It may be beneficial for the health care provider to understand and review with patients that a variety of errors can occur in the restaurant setting, whether from the consumer or the establishment’s personnel (Ahuja and Sicherer, 2007; Furlong et al., 2001). Errors from the consumer could be due to poor communication of the allergy, assumptions made by the consumer about the safety of the foods, and selection of restaurants that may pose additional challenges depending on their allergy (e.g., seafood restaurant for an individual with shellfish allergy). Among 5,149 persons in a self-report registry for peanut and tree nut allergy, composed mostly of children, 13.7 percent reported reactions in food establishments (Furlong et al., 2001). Following a survey of a random subgroup of 129, lack of communication of the allergy was reported for 45 percent of the reactions. Reported rationales included assuming visual inspection would suffice, thinking the allergy was not too severe, and presuming the food should be safe. These findings suggest a benefit for health care personnel in advising patients with food allergy to openly and specifically discuss their allergy with staff of food establishments.

Errors on the part of the restaurant personnel can include misunderstanding of an allergy diagnosis compared with a less dangerous intolerance or preference, poor communication within the establishment, staff failure to prevent cross-contact or to know about hidden ingredients, among others (Ahuja and Sicherer, 2007). Surveys of restaurant personnel in Brighton, United Kingdom (Bailey et al., 2011) and New York City (Ahuja and Sicherer, 2007) showed that restaurant personnel, including chefs, may indicate confidence in providing a safe meal for a food-allergic consumer, but have knowledge deficits about allergy, cross-contact, and general food allergy management. These findings suggest that health care providers should discuss strategies such as encouraging patients with food allergy to review cross contact and hidden ingredients with staff when obtaining restaurant meals (i.e., educate or confirm knowledge of staff).

Travel presents additional potential obstacles for persons with food allergy (Barnett et al., 2012). A lack of global uniform guidelines requires consumers with food allergy to navigate different regulations, or regions with no regulations, internationally. Language barriers may prevent safe communication. Travel to remote regions raises concerns about obtaining safe food and managing a reaction. Several studies have reported allergic reactions on airplanes based on self-report of having unintentionally ingested or been exposed to allergens (Comstock et al., 2008; Greenhawt et al., 2013; Sicherer et al., 1999). These issues, highlighted further in Chapter 8, suggest that individuals and families with food allergy be counseled to consider their allergies when traveling and to call ahead to notify

transportation services, carry medications, ensure safe food is available, and, for younger children, inspect and wipe seating areas for residual food before the child has contact with the space.

Management in Schools and Child Care Centers

Supervision of children and procedures to provide safe foods in early care and education settings, schools, and summer camp settings is required to avoid allergen exposure and to recognize and promptly treat allergic or anaphylactic reactions. A number of recommendations and guidelines have been developed that focus on advice to school personnel, health care providers, patients, and families (CDC, 2013; Eldredge and Schellhase, 2012; Ford et al., 2014; Leo and Clark, 2012; Muraro et al., 2014d; Robinson and Ficca, 2012; Sheetz et al., 2004; Sicherer et al., 2010; Vale et al., 2015; Young et al., 2009). A discussion about approaches to providing a safe experience for children with food allergies when away from home, including the responsibilities of the school staff, is provided in Chapter 8. This chapter focuses on the responsibilities and challenges of the health care provider, parents, and students. These issues also can extend to additional settings away from home, such as religious events, sports, afterschool clubs and camps, among other supervised settings for children (Sampson et al., 2014).

For the child with possible food allergy who attends a school setting, the responsibilities of the child’s physician or health care provider may include confirming the diagnosis, providing a written emergency care plan, providing advice about general management to the family and school personnel, and giving necessary medication prescriptions. As reviewed in Chapter 4, ascertaining a diagnosis and whether a child has a potentially life-threatening food allergy can be difficult. Briefly, these elements for diagnosis include deciphering a true allergy, judging its potential severity, and considering comorbid conditions such as asthma.

The physician or health care provider may work with the patient and family to notify the school about a potentially life-threatening food allergy, including providing a written plan, often referred to as an Emergency Action or Emergency Care Plan for Anaphylaxis or Allergy and Anaphylaxis. Unfortunately, no standard, evidence-based plans have been developed and so numerous forms with many different approaches are used. This may represent a significant gap in providing standard care. Survey studies suggest that an insufficient number of students with food allergy have a management plan, or that the plan may not be followed (Ewan and Clark, 2001; Gupta et al., 2014). No comprehensive studies have been conducted that provide evidence for a validated, brief written emergency plan for individual or general use. Various organizations or schools have

developed plans. Studies have identified key factors that might be included on standardized written plans, or compared plans for determination of preferences, or identified variations in using these plans, but systematic studies are lacking (Banerjee et al., 2007; Ewan and Clark, 2001; Powers et al., 2007; Weiss et al., 2004; Worth et al., 2010). Key features typically include the date, the child’s name, recent weight, identifying information (child’s picture, if provided), specifics about the food allergy or allergies, emergency medications and doses, descriptions of possible symptoms and related treatment instructions, advice to activate emergency services, and family contact information. Development of evidence-based, universal plans could potentially improve understanding and emergency care.

A number of factors must be considered when developing emergency plans for medical management of anaphylaxis and, more specifically, for treatment in a school setting. For example, regarding management in general, no diagnostic test exists to predict or confirm anaphylaxis, and specific symptoms may vary, resulting in treatment quandaries. Although diagnostic features of anaphylaxis have been published, (Sampson et al., 2006b), it is prudent to inject epinephrine (adrenaline) before observing symptoms diagnostic of anaphylaxis. Therefore, the decision to inject epinephrine may vary based on the patient’s history, foods involved, and likelihood of an ingestion of the avoided food at the onset of mild symptoms that could be attributed to other causes and are not (yet) anaphylaxis (i.e., throat discomfort may be an early symptom of a viral infection or an initial symptoms of food allergy). For example, if an allergen was ingested that previously caused anaphylaxis, it may be advisable to inject epinephrine at the time of first symptoms, or if an allergen was definitely ingested and previously known to have caused severe anaphylaxis, it may be advisable to inject epinephrine before symptoms occur (AAAAI BOD, 1998; Sicherer et al., 2010). The supervising adult may need to differentiate a mild allergic symptom from anaphylaxis, deciding when to administer epinephrine. This can be difficult, even for experienced professionals. Current advice emphasizes educating parents and school personnel that (1) antihistamines cannot be depended on to treat anaphylaxis but are adjunctive therapies to treat an allergic reaction, (2) inhaled bronchodilators must not be depended on to treat anaphylaxis but may be given for respiratory reactions, and (3) intramuscular epinephrine is safe and, if a possibility of a severe allergic reaction exists, should be administered (side effects are mild and may include temporary fast heart rate, jitteriness, flushing, or paleness) (Sicherer et al., 2007, 2010). Administration of medications in U.S. schools has been addressed in general guidance documents (Council on School Health, 2009). However, no studies provide sufficient evidence for validation of the options discussed above.

Given the complexity of food allergy diagnosis and emergency treat-

ment, the physician may need to consider whether a licensed health care professional is available to assist the child. When one is not available, a plan that is different from one when a professional is involved must be developed. For example, a licensed health professional may administer an antihistamine for mild allergic symptoms and observe for progression of symptoms before administering epinephrine, whereas a nonlicensed, not medically trained individual may not be expected to make this kind of medical or nursing assessment. In this case, the advice may be to promptly give the epinephrine by auto-injector and call for activation of emergency medical services immediately. No studies have addressed the various approaches upon which to develop best practices in this regard.

In addition to the above issues of medical management, the physician or health care professional should address age-specific concerns (for example, the inability of preschool age children to self-monitor taking unsafe foods or the potential risk-taking activities of adolescents), potential risks, bullying, and general management. Medical identification jewelry is encouraged. Avoidance measures should be discussed and are reviewed in the CDC Voluntary Guidelines for Managing Food Allergies in Schools and Early Care and Education Programs (CDC, 2013). Avoidance advice may vary by age, allergy, developmental abilities, nutritional status, socioeconomic status, and other factors, and counseling may be adjusted according to the needs of the child and the circumstances of the school. However, little information is available to inform best practices on avoidance (Banejee et al., 2007; Cicutto et al., 2012; Vale et al., 2015; Worth et al., 2010). Families and patients should be educated about how and when to administer self-injectable epinephrine, the importance of avoidance strategies (e.g., no food sharing), when to have children notify an adult of any symptoms or if they may have eaten an unsafe food. The diagnosis, treatment plan, and prescriptions should be reviewed periodically and updated at least yearly. Families and schools also need to be alert to the expiration dates on epinephrine auto-injectors.

Finally, the physician and family will need to provide the school with a list of foods to be avoided and possible substitutions. Some school food programs may require physician-recommended substitutions. Additional issues from the community perspective are discussed in Chapter 8 of this report.

Educational Needs

Although it is incumbent upon health care providers to educate patients and families, these providers have noted deficits in understanding food allergy and anaphylaxis management, as described in Chapter 2. Managing food allergy requires educating all those who are involved in measures

associated with avoiding and treating allergic reactions. However, numerous studies suggest that many different stakeholders, including physicians, have deficits in their understanding of these basic concepts (Desjardins et al., 2013; Morawetz et al., 2014). For example, in an Internet survey of medical professionals, only 23 percent recognized risk factors for anaphylaxis and only 55 percent identified a case of anaphylaxis that had no hives (Wang et al., 2014). Another Web-based study of 407 primary care physicians noted a fair allergy and anaphylaxis knowledge base but specific deficits were noted, such as only 23 percent recognizing that cheese is unsafe for those with milk allergy and fewer than 30 percent indicating comfort with laboratory tests or caring for children with food allergies (Gupta et al., 2010b). Surveys of emergency department management of anaphylaxis suggest serious undertreatment of anaphylaxis and lack of referral (Clark et al., 2004). When allergy referral is achieved, previously unknown triggers are often identified (Campbell et al., 2015b).

Surveys of the general public (Gupta et al., 2009) and parents of children with food allergy (Gupta et al., 2010a) also show a variety of knowledge deficits. Studies have identified errors in using epinephrine autoinjectors among patients and health care providers (Arga et al., 2011; Brown et al., 2013; Guerlain et al., 2010; Sicherer et al., 2000). A Canadian survey of 184 respondents of caregivers of children who had experienced a first allergic reaction within the past year identified gaps in the caregivers having received food allergy and anaphylaxis education and coping strategies for fear and anxiety (Abdurrahman et al., 2013). In a qualitative manner, they found three primary areas of deficit: lack of receiving information on recognizing and managing food allergy–related reactions, long wait times to see an allergist, and significant family anxiety. Surveys of school nurses revealed the need for better understanding of emergency plan development, staff education, and delegation and avoidance measures (Carlisle et al., 2010). Surveys of pediatric dietitians (Groetch et al., 2010; Maslin et al., 2014) revealed that they considered they had moderate knowledge for educating families and evaluating safe foods and low knowledge for creating diagnostic food challenges. Knowledge deficits about food allergy also have been noted among child care providers (Greiwe et al., 2015), emergency response providers (Jacobsen et al., 2012), restaurant personnel (Ahuja and Sicherer, 2007; Bailey et al., 2011), and teachers (Ercan et al., 2012; Polloni et al., 2013). Overall, stakeholders are currently insufficiently educated and seek more information on food allergy.

Studies suggest that educating health care providers is valuable and that patients and their families may benefit from being directed to various educational resources. A number of studies report successful educational materials or programs for various stakeholders, including in-person and online programs, many of which have not been validated (Bailey et al.,

2014; Bansal et al., 2005; Camargo et al., 2007; Cavanaugh and Strickland, 2011; Chokshi et al., 2015; Desai et al., 2015; Hernandez-Trujillo and Simons, 2013; Reeves et al., 2015; Rosen et al., 2014; Sasaki et al., 2015; Shah et al., 2013; van Os-Medendorp et al., 2015; Wahl et al., 2015; White et al., 2015; Yu et al., 2008). One study found that providing simple guidelines improved anaphylaxis management in the emergency department (Desai et al., 2015). In one program that health care professionals can use with parents of children with food allergy (Sicherer et al., 2012), significant improvements were seen in the correct number of auto-injector activation steps, comfort with using the auto-injector, knowledge test scores, and the annualized rate of allergic reactions fell on average from 1.77 (historical) the year prior, to 0.42 (P<0.001) after the program. A number of smart-phone and tablet applications are also emerging for managing food allergy (Cuervo-Pardo et al., 2015).

Food anaphylaxis can occur in any setting but proper emergency management can resolve a life-threatening occurrence. Therefore, the public, particularly first responders and aiders, need to be prepared to assist in such food-related severe reactions. There is not, however, a national standardized curriculum that includes required elements for emergency care training. Overall, food allergy anaphylaxis is not included in training curricula of organizations that offer various certifications on emergency training or specialized training for professionals such as pediatric specialization for child care providers or training for Emergency Medical Service personnel.

In summary, education of stakeholders is key for food allergy management because knowledge deficits are significant. There is a clear unmet need for education. Evidence indicates that adopting a multidisciplinary clinical approach and providing educational materials may improve knowledge, correct use of epinephrine, and reduce reactions. Although various educational programs are available or in development, most have not been extensively studied. Studies on widespread implementation also are lacking.

High-Risk Groups

Several guidelines (e.g., Muraro et al., 2014b; Sampson et al., 2014) emphasize that certain factors may increase the risk for anaphylaxis. Examples of factors that may increase risks include coexisting asthma, allergies to specific foods (e.g., peanut, tree nuts), degree of sensitivity and extent of eliciting factors (e.g., illness, exercise, medications, alcohol). The relative contributions of all of these are not established. Risk factors identified in case series of fatal food allergic reactions include adolescence or young adult age group, comorbid asthma, ingestion of peanut or tree nuts (although fatal reactions can occur from other allergens, such as

milk), delayed treatment with epinephrine, lack of skin symptoms (perhaps resulting in delayed recognition and treatment), and previously diagnosed food allergy (Bock et al., 2001, 2007; Pumphrey, 2000; Pumphrey and Gowland, 2007; Sampson et al., 1992). The AAAAI Guidelines (Sampson et al., 2014) suggests discussing self-care management techniques especially with high-risk patients, described as adolescents, young adults, and patients with asthma.

Adolescents and young adults, including those in college, may be at higher risk of fatal food-induced anaphylaxis for a variety of reasons (Akeson et al., 2007; Greenhawt et al., 2009; Macadam et al., 2012; Marrs and Lack, 2013; Monks et al., 2010; Mullins, 2003; Noimark et al., 2012; Sampson et al., 2006a). They may not understand or recognize, or may deny symptoms indicating anaphylaxis. For example, in a survey of 174 adolescents with food allergy, 61 percent did not report having anaphylaxis but described symptoms such as throat swelling, trouble breathing, and loss of consciousness (Sampson et al., 2006a). In this same study, risk-taking behaviors included not always carrying epinephrine (39 percent), purposefully ingesting unsafe food (54 percent), and ingesting foods with advisory labeling for their allergen (42 percent). The motivation behind risk-taking behaviors may include poor understanding of risk, convenience, not wanting to feel different from peers, bullying, lack of recollection of allergic reactions, success having survived self-resolving reactions without the need for treatment, fear of injections, overreliance on emergency medications on hand to justify unsafe eating behaviors, and other behavioral and psychosocial factors (Akeson et al., 2007; Greenhawt et al., 2009; Macadam et al., 2012; MacKenzie et al., 2010; Marrs and Lack, 2013; Monks et al., 2010; Noimark et al., 2012; Sampson et al., 2006a). Potential for interventions also are noted in several studies. In one study, 68 percent of adolescents with food allergy indicated a belief that educating their friends would make living with food allergy easier (Sampson et al., 2006a). In another study of adolescents with food allergy, adherence to self-care was reported by 16 percent of participants, and was more likely if the adolescents belonged to an allergy support group (odds ratio [OR]: 2.54; 95% confidence interval [CI]: 1.04-6.20), had a written management plan (OR: 3.22; 95% CI: 1.18-8.81), perceived having a more severe allergy (OR: 1.24; 95% CI: 1.01-1.52), and perceived fewer management barriers (OR: 0.87; 95% CI: 0.79-0.96) (Jones et al., 2015). Approaches for providing care and better education have not been systematically studied, but suggestions have included targeting knowledge, preparedness, empowerment, and beliefs (Marrs and Lack, 2013).

Advice on Allergens in Nonfood Items and Alcoholic Beverages

Allergens in Pet Foods, Cosmetics, and Topical Products

A variety of noningested products include allergens, which requires caution on the part of consumers when allergen disclosures may not be included. Examples include pet foods containing milk, soy, fish, or nut ingredients, and lotions with nut ingredients. Most of these products are not ingested, so the risk of anaphylaxis would be relatively low but studies have not delineated the risks. These products have no labeling requirements relating to food allergens. Physicians may discuss these potential risks with patients who have food allergy, especially with toddlers who may otherwise have access to these products and could ingest them accidentally.

Allergens in Vaccines, Medications, and Dietary Supplements

Physicians and patients with food allergy must consider potential food allergen exposures in vaccines, medications, and dietary supplement products (e.g., vitamins, probiotics), which are not regulated by labeling laws. Also, excipients (i.e., substances added to medications to improve various characteristics) may be food or derived from foods (Kelso, 2014). These include milk proteins; soy derivatives; oils from sesame, peanut, fish or soy; and beef or fish gelatin. The medications involved include vaccines; anesthetics; and oral, topical, and injected medications. With perhaps the exception of gelatin, reactions appear to be rare overall, likely because little residual protein is included in the final preparation of these items. The specific risk for each medication is not known.

Vaccines also may contain food allergens, such as egg protein or gelatin. Expert opinion based on many studies suggests that the yearly influenza vaccination and the measles, mumps, and rubella vaccines should not be deferred based on egg allergy (e.g., Turner et al., 2015). In contrast, the yellow fever and rabies vaccines should not be given to persons with severe egg allergy unless testing with the vaccine is undertaken first (Kelso et al., 2012, 2013).

Allergens in Alcoholic Beverages

Allergic or allergic-like reactions can occur from alcoholic beverages. These products are not included in allergen labeling laws and counseling of patients may be warranted. However, the literature on the allergenicity of alcoholic beverages is sparse. Persons with alcohol dehydrogenase deficiency may experience dose-related symptoms that mimic allergy, including flushing, nausea, vomiting, and sometimes wheezing. Sulfites, often found

in wine, may induce asthma symptoms. Wines may be clarified by processes that use allergens such as egg, but the final product may not likely contain residual protein (Rolland et al., 2008). Beer may have residual proteins from barley or other grains that can trigger reactions (Quercia et al., 2012). Distilled alcohol should be free from protein. Many alcoholic beverages are made from potential allergens, for example amaretto from almonds, frangelico from hazelnuts, and Irish cream from milk, but the residual allergenicity of these products has not been studied.

EMERGENCY MANAGEMENT OF ALLERGIC REACTIONS

The physician must counsel patients with food allergy, and their families, on recognizing and treating food-induced anaphylaxis. The following discusses some of the challenges involved in diagnosis and treatment of anaphylaxis at the level of first aid and physician care. The previous section “Management in Schools and Child Care Centers” includes additional information regarding written emergency plans and emergency medical identification jewelry.

Definition of Anaphylaxis, Diagnosis, and Differential Diagnosis

Anaphylaxis has been described as a severe, life-threatening, generalized or systemic hypersensitivity reaction (Muraro et al., 2014a). Life-threatening breathing, airway, or circulatory problems may occur and skin and mucosal changes usually, although not always, occur. A consensus definition was proposed in 2006, describing anaphylaxis as “a serious allergic reaction that is rapid in onset and may cause death” (Sampson et al., 2006b, p. 392). Diagnostic criteria based on consensus were published in 2006 (Sampson et al., 2006b) and some validation has been performed (Campbell et al., 2012; Harduar-Morano et al., 2010). Diagnosis may need to differentiate anaphylaxis from fainting, cardiac events, mild allergic reactions, asthma, choking, panic attacks, and many other ailments. However, no simple tests exist to confirm anaphylaxis or to predict those at risk. Serum tryptase, a mediator released from mast cells, may not be increased with food-induced anaphylaxis, although severity of the episode and differences from baseline may be relevant (De Schryver et al., 2016; Lin et al., 2000a; Sahiner et al., 2014; Sala-Cunill et al., 2013; Wongkaewpothong et al., 2014). Histamine measurements are difficult to obtain. As reviewed previously, allergy tests are not good predictors of severity of reactions. Overall, anaphylaxis is a clinical diagnosis and no rapid diagnostic test is available.

Nature of Anaphylaxis

Anaphylaxis involves more than one organ system (e.g., skin, respiratory tract, and/or gastrointestinal [GI] tract) (Boyce et al., 2010). The skin is involved in 80 to 90 percent of episodes, respiratory symptoms in up to 70 percent, GI in up to 40 percent, and cardiovascular symptoms in up to 35 percent (Boyce et al., 2010; Dhami et al., 2014; Lieberman et al., 2015; Muraro et al., 2014a; Sampson et al., 2014). Symptoms include flushing, pruritus, hives (urticaria), nasal congestion and rhinorrhea, throat itching and swelling (edema), choking, wheezing, coughing, trouble breathing, altered breathing sounds or trouble speaking, cramping abdominal pain, nausea, vomiting, diarrhea, dizziness, high or slow heart rate, sleepiness, confusion, loss of consciousness, anxiety, feeling of doom, seizure, and uterine cramps.

Food-induced anaphylaxis typically occurs within minutes to several hours of ingestion of the food (but may be longer for mammalian meat, alpha-gal-related reactions (Boyce et al., 2010; Sampson et al., 2014; Tripathi et al., 2015). The reaction usually develops and resolves completely within hours, but a biphasic course has been described where symptoms resolve but recur hours later, a phenomenon that is described for 1 to 20 percent of cases (Alqurashi et al., 2015; Ellis and Day, 2007; Lee and Greenes, 2000; Lee et al., 2015b; Lieberman, 2005; Mehr et al., 2009; Sampson et al., 1992). Biphasic reactions may be more likely with severe or undertreated reactions, but are unpredictable, and observation in an emergency department for at least 4 to 6 hours is recommended (Boyce et al., 2010). Rarely, symptoms can last for many hours or days (Sampson et al., 1992). Deaths have been reported from 30 minutes to 2 hours after exposure (Bock et al., 2001, 2007; Sampson et al., 1992). No biomarkers are available that adequately predict severity or whether a biphasic reaction will develop. Reactions could be worse, milder, or similar from time to time, presumably because of many variables including overall sensitivity, amount of allergen ingested, and other factors.

Risk Factors (Asthma, Certain Foods, Cofactors) and Risk Assessment

A number of comorbid diseases may affect the severity and treatment response of anaphylaxis (Boyce et al., 2010; Dhami et al., 2014; Lieberman et al., 2015; Muraro et al., 2014a; Sampson et al., 2014). Asthma is a significant risk factor for death, especially in adolescents and young adults (Bock et al., 2001, 2007; Pumphrey, 2000; Pumphrey and Gowland, 2007; Sampson et al., 1992). Cardiac disease is a risk factor for middle-aged or older adults (Pumphrey, 2000; Pumphrey and Gowland, 2007). Allergies to some foods are associated with more severe reactions (e.g., peanut, tree

nuts, milk, fish, shellfish, seeds, and egg) than others (fruits and vegetables). Additional risks for more severe reactions include underlying mastocytosis and lung disease diagnosis. Various medications may affect response to treatment, including beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors, and alpha adrenergic blockers. No simple means exist to predict the severity of reactions or to clearly identify an individual at risk.

Medical Treatment of Anaphylaxis

Epinephrine, typically prescribed as auto-injectors for self-injection for first aid management, is first-line therapy for food-induced anaphylaxis and is recommended to be injected intramuscularly (anterolateral thigh into the vastus lateralis muscle) (Boyce et al., 2010; Lieberman et al., 2015; Muraro et al., 2014a; Sampson et al., 2014). Epinephrine should be administered promptly for anaphylaxis and when clinical features are likely to evolve into anaphylaxis (AAAAI BOD, 1994; Muraro et al., 2014a). Delay in providing therapy with epinephrine is associated with increased risk of death and morbidity. Epinephrine has a variety of actions that improve breathing and circulation and may reduce the release of additional inflammatory mediators. Treating anaphylaxis with epinephrine has no absolute contraindications.

A Cochrane Systematic Review (Sheikh et al., 2012a) of the effectiveness of epinephrine auto-injectors in relieving respiratory, cardiovascular, and other symptoms during anaphylaxis in the community setting sought randomized or quasi-randomized trials comparing auto-injectors to no intervention or other interventions and found no qualifying studies out of 1,328 references that were reviewed. Nonetheless, the conclusion was to recommend epinephrine auto-injectors as the most effective first-line treatment for anaphylaxis in the community, with a recommendation for trials comparing different doses and devices as well as syringe and ampule.

According to the NIAID/NIH-supported Guidelines, a prescription for an epinephrine auto-injector, typically two doses, should be given to those who have experienced anaphylaxis as well as patients with diagnosed food allergy who have asthma and those with allergy to foods that typically cause severe reactions (e.g., peanut, tree nuts, fish, shellfish). A prescription for anyone with a diagnosed food allergy may be considered because subsequent reaction severity is hard to predict (Boyce et al., 2010). The EAACI Anaphylaxis Guidelines (Muraro et al., 2014b) additionally comment upon a prescription being indicated when a person has had previous mild to moderate symptoms from trace food exposure, mild to moderate symptoms to a food and travel to areas remote from medical care is planned, and for teenagers or young adults with food allergy (excluding oral allergy syndrome). The AAAAI Practice Parameter on anaphylaxis discusses additional con-

siderations, such as allergy to mustard, peach, or apple, for those patients in Mediterranean regions (who tend to have more severe reactions to these fruits), and people having past reactions with throat tightness, those having food allergy and airway anatomy that predisposes to obstruction, or those having contact allergic reactions to specific foods. This document also concluded that physician discretion is needed (Lieberman et al., 2015).

Consensus has emerged on the use of premeasured auto-injector doses of 0.15 mg for those weighing 16.5 (7.5 kg) up to 55 pounds (25 kg), and a dose of 0.3 mg for those 55 pounds and greater (Boyce et al., 2010; Muraro et al., 2014a; Sampson et al., 2014). Controversy exists regarding the auto-injectors use for infants weighing less than 7.5 kg (or less than 10 kg in some guidelines [Boyce et al., 2010, Sampson et al., 2014]) and for individuals with obesity (Sicherer et al., 2007; Simons et al., 2014, 2015). Although dosing at 0.01 mg/kg epinephrine intramuscularly has been recommended, the ideal dose has not been determined through studies (Lieberman et al., 2015). Additional studies and potentially a wider range of fixed-dose auto-injectors may be beneficial.

First aid management also includes activating emergency services (calling for help, dialing 911 or equivalent), evaluating airway breathing and circulation, and providing cardiorespiratory resuscitation, if needed. It may be beneficial to place the patient in a recumbent position with the legs elevated if tolerated (although bringing a patient to a standing position may result in death, and caution is needed during transport (Pumphrey, 2003). The patient may require more than one dose of intramuscular epinephrine, as studies suggest this may occur in 10 to 20 percent of cases (Jarvinen et al., 2008; Oren et al., 2007). The intramuscular epinephrine dose can be repeated (e.g., in approximately 5 minutes from the last dose), as warranted by symptoms (Muraro et al., 2014a). Side effects of epinephrine may include restlessness, headache, dizziness, palpitations, pallor, flushing, and tremor. Rarely, epinephrine can lead to severe side effects, such as myocardial infarction or intracranial hemorrhage, but these severe side effects almost exclusively occur from overdose, which is more likely if errors in intravenous administration occur, rather than intramuscular injection from auto-injectors (Campbell et al., 2015a).

Additional treatment of anaphylaxis is considered adjunctive to epinephrine and may include bronchodilator medications, H1 and H2 antihistamines, corticosteroids, vasopressors, glucagon, atropine, supplemental oxygen, intravenous fluids, and patient positioning (Boyce et al., 2010; Lieberman et al., 2015; Muraro et al., 2014a; Sampson et al., 2014). Most of these adjunctive therapies would be available following first aid management and would be administered by emergency personnel or by emergency department staff.

Systemic antihistamines are often used during anaphylaxis. Systematic

reviews to assess the benefit or harm of H1 antihistamines for the treatment of anaphylaxis have been conducted. Randomized and quasi-randomized controlled trials to compare this therapy with placebo or no intervention have been sought. However, no studies have satisfied inclusion criteria (Nurmatov et al., 2014b; Sheikh et al., 2007). The medications presumably help to relieve cutaneous symptoms but no studies regarding effect on other symptoms of anaphylaxes or progression of reactions have been conducted. Combination treatment with H1 and H2 antihistamines may have additional efficacy compared to H1 antihistamines alone for cutaneous symptoms (Lin et al., 2000b; Runge et al., 1992). Oral (in preference to intravenous) administration is recommended for relief of cutaneous symptoms (Ellis and Brown, 2013; Muraro et al., 2014a) to avoid hypotension related to rapid intravenous administration. The onset of action of antihistamines (e.g., liquids, rapid disintegrating tablets) is approximately 30 minutes. Studies to determine the benefit or harm of antihistamines in anaphylaxis would be useful.

Oral or intravenous glucocorticoids are often used in anaphylaxis to theoretically prevent protracted symptoms or late onset of symptoms and also to address concomitant asthma. A systematic review was undertaken with the intention to perform a meta-analysis to assess benefits and harms of glucocorticoid treatment during anaphylaxis, but no randomized or quasi-randomized controlled trials comparing glucocorticoids to any control were identified and so no meta-analysis could be undertaken (Choo et al., 2012). Therefore, therapy with glucocorticoids, which have a slow onset of action, are used in anaphylaxis without clear evidence and are based on expert opinion (Boyce et al., 2010; Muraro et al., 2014a; Sampson et al., 2014). Studies on the utility of glucocorticoids in anaphylaxis could inform therapeutic approaches.

No consensus in the literature exists on the optimal time for observation of the patient who has experienced anaphylaxis, although 4 to 6 hours has been suggested, or longer if the patient experienced hypotension (Boyce et al., 2010; Muraro et al., 2014a; Sampson et al., 2014).

Post-Anaphylaxis Long-Term Management

Based on current guidelines, discharge planning or long-term management should include a written anaphylaxis emergency action plan, encouraging medical identification jewelry, and having epinephrine auto-injectors (typically two) always available, a plan for monitoring auto-injector expiration, a plan for arranging further evaluation as needed, printed information about anaphylaxis and its treatment, and consideration for referral to specialist for further evaluation. It also is recommended to have instructions on the proper use of epinephrine auto-injectors and indications for use, advice

about allergen avoidance, and additional information regarding a dietitian consult and support groups (Boyce et al., 2010; Lieberman et al., 2015; Muraro et al., 2014a; Sampson et al., 2014). As reviewed above, discharge and long-term management of patients with food allergy who are at risk for anaphylaxis has some potential pitfalls. Nutritional and psychological concerns are described below.

NUTRITIONAL CONSIDERATIONS

Adequate nutrition is important for normal child development and growth. When allergen avoidance is the one recommendation to minimize the risk of an allergic reaction, children could end up deficient on specific nutrients or calories if attention to their nutrition is not considered.

The NIAID/NIH-supported Guidelines suggest nutritional counseling and regular growth monitoring for all children with food allergies (Boyce et al., 2010) and the EAACI Guideline suggested that, ideally, the patient would receive proper counseling by a dietitian with specific competence in food allergy, recognizing this is particularly important for infants and children and may vary by age and foods avoided (Muraro et al., 2014b).

The most common allergenic foods contain nutrients whose removal may reduce diet quality (i.e., lead to nutrient deficiencies) and, therefore, may be detrimental to health, particularly for an infant or child. For example, cow milk has protein, fat, calcium, vitamin D, and riboflavin; wheat in fortified cereals contains carbohydrates, iron, thymine, niacin, riboflavin, and folate; egg includes protein, fat, iron, and riboflavin; and fish and shellfish are sources of protein, fat, and omega-3 fatty acids. When cow milk is avoided, substitutions are typically needed to account for lost nutrients (Fiocchi et al., 2010). For example, an infant or toddler who does not use cow milk may require breast milk or a human milk substitute, and older toddlers may require a calcium supplement and/or fortified alternative beverages, such as soy milk or rice, almond, oat, or coconut beverages, depending on other components of the diet and as tolerated. However, these beverages are not equivalent to cow milk in terms of fat, protein, calories, and other essential nutrients (Groetch et al., 2013). Specifically, an infant with a diagnosed cow milk allergy will typically tolerate formulas approved for use in these circumstances, such as extensively hydrolyzed casein–based or amino acid–based formula, or soy formula, as medically necessary following a diagnostic evaluation. However, partially hydrolyzed milk–based formula is not typically appropriate for an infant with a diagnosed cow milk allergy (Lee et al., 2015a). Infants with food allergy may have nutritional concerns related to their elimination diets or to underlying chronic illness. For example atopic dermatitis or GI inflammation can interfere

with nutrient absorption or result in increased caloric needs (Jarvinen et al., 2013).

No RCTs have addressed whether food allergen avoidance affects growth and nutritional status of infants and children. Multiple studies, primarily observational and cross-sectional, suggest that food allergy may be associated with impaired growth (Cho et al., 2011; Christie et al., 2002; Flammarion et al., 2011; Hobbs et al., 2015; Isolauri et al., 1998; Mehta et al., 2014; Meyer et al., 2012, 2014; Mori et al., 2015; Mukaida et al., 2010; Nachshon et al., 2014; Vieira et al., 2010). It has particularly been noted that growth may be impaired in those avoiding cow milk (Hobbs et al., 2015; Isolauri et al., 1998; Mehta et al., 2014; Mukaida et al., 2010; Tiainen et al., 1995). For example, Tiainen et al. (1995) compared 18 children (mean age 2 years, range 1 to 3.5 years) with cow milk allergy and 20 healthy controls and found that although total energy intake between the two groups did not differ, the children with milk allergy had lower protein and higher fat intake compared to controls, and the allergic children also had a lower height for age percentile (–0.6 versus 0.2 SD units; P<0.05). Long-term outcomes for those on a childhood milk avoidance diet can include increased risk of reduced bone mineral density and increased risk of early osteoporosis (Nachshon et al., 2014). A small (N=39) prospective study from the United Kingdom found that milk avoidance in early life can have a long-term effect on food intake and preferences (Maslin et al., 2016).

Having multiple food allergies appears to put children at increased risk of decreased growth, due to the reduced food and total energy intake (Cho et al., 2011; Christie et al., 2002; Flammarion et al., 2011; Hobbs et al., 2015; Meyer et al., 2012, 2014; Mukaida et al., 2010; Vieira et al., 2010). For example, Christie et al. compared children with food allergy to healthy controls and found that children with two or more food allergies were shorter than those with one, and children with cow milk or multiple food allergies were less likely to consume sufficient dietary calcium (Christie et al., 2002). Meyer et al. noted that children with food allergies were more underweight than the general UK population, which was linked to the number of foods excluded (Meyer et al., 2014). However, they also noted cases of obesity despite dietary elimination. A systematic review of nutrient intake and growth in children with multiple IgE-mediated food allergies identified six studies and concluded that “children with multiple food allergies have a higher risk of impaired growth and may have a higher risk of inadequate nutrient intake than children without food allergies” (Sova et al., 2013, p. 669). Although data are limited (Berni Canani et al., 2014; Christie et al., 2002), dietary counseling can potentially improve macro and micro nutrient intake and growth outcomes without evidence of inducing overweight status. Evidence-based specific dietary guidance for children with food allergy is lacking (Groetch et al., 2013; Meyer et al.,

2012). However, the data suggest that by individualizing dietary counseling, dietary intakes and nutritional status can be improved and growth impairment may be prevented.

QUALITY OF LIFE AND MENTAL HEALTH CONSIDERATIONS

Daily management of food allergy is focused on avoiding trigger foods and recognizing and managing allergic reactions, some of which are life-threatening. These considerations practically affect the routine of daily living and also carry psychological burdens that can result in anxiety and stress. Measurement of health-related quality of life (HRQL) helps determine the impact of disease on an individual, which may vary among individuals even if disease severity is similar. Tools to measure HRQL may be generic or disease specific. Generic instruments allow comparison between disorders, while disease-specific instruments are more sensitive for measuring the burden of disease and identifying changes caused by interventions.

A systematic review was undertaken to identify validated instruments specific to food allergy disease (Salvilla et al., 2014). Seventeen eligible studies were retrieved and seven disease specific HRQL instruments were subjected to detail quality appraisal. These seven were found to have robust psychometric properties (Cohen et al., 2004; DunnGalvin et al., 2008; Flokstra-de Blok et al., 2008, 2009a,b; MacKenzie et al., 2012; Resnick et al., 2010) and to be suitable for use in children, adolescents, parents and caregivers, and adults. The authors also concluded that further work is required to understand clinically important differences in score appraisal of patients with food allergy. Using this systematic review, guidelines were developed for using specific instruments based on the type of food allergy, research or clinical applications, inclusion or exclusion of comorbidities, patient age, language and cultural issues, the preferred respondent, and target population (Muraro et al., 2014c). This review pointed out that the instruments have been used in research settings only to provide quantitative information on the HRQL of patients with IgE-mediated food allergy and to assess the effect of interventions and determine outcomes. Studies to recommend use of these instruments at the individual patient level are insufficient. Additionally, the review offered a number of research recommendations, including a need to: determine optimum methods of administration, frequency, and interpretation; identify which instruments, if any, are valid to guide clinical practice of individual patients; determine efficacy of the instruments for evaluating medical and technological advances, patient satisfaction and quality of care, and health and regulatory policy; include these instruments to explain different pathways in the development, expression, and impact of chronic diseases; articulate norms for age, sex, and country or culture; explain the relationship between responses to both proxy and

self-report measures; develop optimum methods for evaluating measures in patients with comorbid conditions; and, determine how quality-adjusted life years for food allergy can be developed to help inform policy.

Aside from validated HRQL instruments, the practical emotional concerns of daily management of food allergies can result in distress. Indeed, the NIAID/NIH-supported Guidelines recommends that patients with food allergy and their caregivers be given information on food allergen avoidance and emergency management that is age and culturally appropriate because management can have substantial daily consequences, including anxiety and diminished quality of life (Boyce et al., 2010). Food-specific HRQL instruments generally query on issues such as holiday plans, restaurants, social activities, time for preparing meals or other meal-related events, taking precautions, troubles in having to carry medications, worry about health issues, not being able to get help for a reaction, other’s lack of understanding about the allergy, attending school or work activities safely, having a normal life, anxiety, and worry about the allergy or reactions (Cohen et al., 2004; DunnGalvin et al., 2008; Flokstra-de Blok et al., 2008, 2009a,b; MacKenzie et al., 2012; Resnick et al., 2010). The degree of impact on HRQL can vary based on knowledge of food allergies, age, having had experiences such as emergency room visit for anaphylaxis, an injection of epinephrine, or multiple food allergies, or allergies to specific foods (e.g., milk or egg compared to peanut or tree nut), and the impact can be complex due to interactions among various factors (Springston et al., 2010; Ward and Greenhawt, 2015; Wassenberg et al., 2012).

Various factors may affect the distress, anxiety, and psychological aspects of a food allergy diagnosis and management. Additionally, the impact may vary based on age, role, and time living with a diagnosis. Compared to mothers of children without chronic illness, mothers of children with food allergy have increased anxiety and stress (Lau et al., 2014). For example, a study of families with a child having peanut allergy revealed that mothers compared to fathers reported lower psychological and physical quality of life and more stress and anxiety (King et al., 2009). This study also found that children with food allergy had greater separation anxiety than their siblings. Another study noted that mothers of children with food allergy were more empowered than fathers of children with food allergy, but empowerment was not associated with higher HRQL (Warren et al., 2015). One study found that maternal anxiety and a child’s attitude toward food allergy were associated with child distress for children ages 8 to 17 years (Lebovidge et al., 2009). Another study found that child anxiety and parental stress significantly predicted parental report of their child’s HRQL, and that child anxiety, parenting stress, length of diagnosis, and receiving epinephrine predicted self-reported HRQL (Roy and Roberts, 2011). A study using various scales to determine anxiety and depression found that

among parents being evaluated for a first-time allergy clinic appointment for suspected food allergy in their child, 33 percent reported mild to severe anxiety and 18 percent reported depression, with no significant change 1 month after the visit (Knibb and Semper, 2013).

Studies have focused on teens and young adults as well. A small qualitative study of adolescents and their parents found that having a child with anaphylaxis can have a significant long-term psychological impact on the parents, and in some cases, this anxiety may be transferred to the adolescents (Akeson et al., 2007). In a large study of adolescents (N=1,420) followed longitudinally, having food allergy was associated with more symptoms of separation and generalized anxiety, attention deficit and hyperactivity disorder, and anorexia nervosa. Over time, adolescents with food allergy experienced increases in generalized anxiety disorder and depression, but having food allergy was not associated with a higher likelihood of having a diagnosed psychiatric disorder (Shanahan et al., 2014). An online study of 86 food-allergic and 344 healthy adults ages 18 to 22 years evaluated autonomy, anxiety, depression, and perception of parental behavior. The study indicated that, although food allergic young adults did not differ from healthy ones, those who experienced anaphylaxis described their disease as more severe, were more worried, and indicated their parents as more protective then those who had not experienced anaphylaxis (Herbert and Dahlquist, 2008). Additionally, for adolescents and young adults, having a food allergy may be associated with dating anxiety, interference with physical intimacy, and fear of a negative evaluation by peers (Hullmann et al., 2012).

Bullying has been another focus of study among psychosocial aspects of food allergy. Episodes of bullying appear to be more common among children with food allergy compared to peers and can take the form of verbal and physical events (Lieberman et al., 2010). Bullying is significantly associated with decreased quality of life and increased distress in parents and children. Parents often may not know about their child being bullied (Shemesh et al., 2013). When parents were aware of bullying, the child’s quality of life was better and distress was reduced. Food-related bullying often persists over time, although it is less likely to continue if parents intervene (Annunziato et al., 2014). The AAAAI Guidelines specifically suggests that physicians inquire about behavioral changes because of food allergy–related bullying (Sampson et al., 2014).

Overall, the relationship of a chronic disease such as food allergy and psychosocial problems is complex. A systematic review and meta-analysis of 43 studies suggested a positive association between psychosocial factors and future atopic disorders and current atopic disorders and future poor mental health, but studies of food allergy were insufficient to comment on this disease separately (Chida et al., 2008). Determinants of food allergy–

related cognition, emotion, and behavior are complex and understudied (DunnGalvin et al., 2009).

Interventions pertaining to reducing the psychosocial impact of food allergy are few. It appears that food allergy interventions themselves can result in improvement. For example, measures of food-specific HRQOL showed improvement for those on desensitization therapy in small or uncontrolled studies (Arasi et al., 2014; Carraro et al., 2012; Factor et al., 2012; Otani et al., 2014). Also, anxiety may decrease and HRQL may improve following a diagnostic OFC, whether the outcome confirms an allergy or not (Franxman et al., 2015; Knibb et al., 2012; Soller et al., 2014; van der Velde et al., 2012; Zijlstra et al., 2010). However, no comprehensive, evidence-based protocols exist for the clinical management of psychosocial concerns related to food allergy, and studies are few. Availability of a 24-hour helpline for expert management improved quality of life for participants randomized to this intervention (Kelleher et al., 2013). A pilot study of a telephone-based intervention teaching parents self-regulation for chronic disease management resulted in improvement in some components of HRQL (Baptist et al., 2012). Data to understand the value of support groups for food allergy are limited (Sharma et al., 2012).

Referral to a mental health professional would presumably be of value, if indicated, to improve psychosocial health concerns. Unfortunately, one study of mental health screening of families with food allergy failed to result in a greater consultation rate with a mental health professional compared to a referral by the patient’s allergist (Shemesh et al., 2015). An expert review on the topic of addressing the psychosocial aspect of food allergy on a patient-level basis suggested that medical providers can validate feelings, normalize the challenge of balancing management with participation in daily activities, and provide education about food allergy and its psychosocial impact, with referral to a mental health expert when indicated (Herbert et al., 2016).

In conclusion, food allergy may affect different aspects of mental health and HRQL. Health professionals should address these issues. However, more information is needed to refine understanding about identification, prevention, and management of these issues.

TREATMENT MODALITIES UNDER INVESTIGATION

The following summarizes approaches under investigation to treat food allergy. This is not meant to be a comprehensive review of risks and benefits of these approaches, nor a compendium of all approaches under study, but rather an overview with summaries of expert reports and suggested additional references. The committee did not make an assessment in regard to

which treatment modalities have more promise in the future nor where the research gaps exist.

A number of food allergy treatment strategies are under investigation. Examples that are furthest along in study and are allergen-specific include oral, sublingual, and epicutaneous immunotherapy.

Oral immunotherapy (OIT) involves ingesting the food allergen in gradually increasing amounts. Protocols typically begin with ingestion of trace amounts, building up to a small dose on a first day and then increasing the dose, which is taken daily, on a biweekly basis toward a daily “maintenance” dose. Sublingual immunotherapy (SLIT) takes a similar approach but the allergen is retained for a period under the tongue and much lower doses are used compared to OIT. Epicutaneous immunotherapy (EPIT) involves placement of a membrane impregnated with allergen on the skin. These therapies are often evaluated in context of promoting “desensitization” to the targeted food allergen. That is, these treatment approaches may raise the threshold of reactivity while the therapy is in progress, while cessation of therapy may result in loss of protection. A curative therapy would not depend upon daily treatments to maintain a threshold where the food can be ingested without concerns for dose ingested or other factors that may alter the safe ingestion of the food (e.g., concomitant exercise, illness). Approaches that are not allergen-specific also have been suggested. For example, omalizumab is a humanized monoclonal antibody against IgE that is approved for use in recalcitrant allergic asthma and for chronic hives. It may increase the threshold of reactivity to allergens and may, in co-administration with OIT, allow more rapid dosing with fewer symptoms (Begin et al., 2014; Schneider et al., 2013; Wood et al., 2015). Studies with a similar agent suggested an increased threshold to peanut during oral food challenges (Leung et al., 2003).

The 2010 NIAID/NIH-supported Guidelines concluded that allergen-specific immunotherapy is not recommended, and also did not recommend immunotherapy with cross-reactive allergens (i.e., pollen allergens to treat oral allergy syndrome) (Boyce et al., 2010). The 2014 EAACI Guidelines concluded that allergen-specific immunotherapy is promising, but is associated with risks, including anaphylaxis and is not recommended for routine clinical use (Muraro et al., 2014b). These Guidelines (p. 1019) also stated that “the use of anti-IgE alone or in combination with specific immunotherapy is currently not recommended . . . although it represents a promising treatment modality.” In addition, the 2010 NIAID/NIH-supported Guidelines and the EACCI Guidelines both recommend not using pollen immunotherapy to primarily treat food allergy. The AAAAI Guidelines similarly concluded that immunotherapeutic approaches such as OIT show promise, but are not ready for implementation in clinical practice because

of inadequate evidence of therapeutic benefit over risks (Sampson et al., 2014).

The field of allergen-specific immunotherapy is rapidly progressing. A number of systematic reviews and meta-analyses have addressed the utility of immunotherapy (primarily OIT and SLIT) for food allergy. A 2012 meta-analysis of milk OIT identified five trials. The authors noted the poor quality of the trials and concluded that treatment could lead to desensitization in a majority of individuals. Although most were mild, a major drawback was the frequency of side effects (Yeung et al., 2012). A 2014 systematic review and meta-analysis of milk oral OIT identified six qualifying articles and concluded that it was effective for treating IgE-mediated cow milk allergy because significantly more patients were desensitized on treatment compared to those on an avoidance diet. The treatment was considered reasonably safe because side effects were mild to moderate and intramuscular epinephrine was rarely required (Martorell Calatayud et al., 2014). A 2012 review and meta-analysis of peanut OIT (Sheikh et al., 2012b) identified six qualifying studies with 85 participants, but given the case series design of all the studies, they were considered to have high risk of bias.⁴ The authors noted suggestive evidence that treatment could increase the threshold for many participants but that adverse reactions were common. Although most were minor, some were potentially life-threatening. They concluded that the treatment was promising for short- or medium-term management of carefully selected patients, but that more robust studies were needed and that OIT should not be administered outside of carefully designed clinical trials. A 2014 meta-analysis (Sun et al., 2014) of RCTs of peanut OIT and SLIT identified three studies with a total of 86 participants. These immunotherapies were determined to have a positive effect on peanut allergy (OR: 38.44; 95% CI: 6-246). The authors cautioned that the findings were based on a small number of trials and larger, well-designed and double-blind RCTs are needed. A 2013 review of pediatric SLIT (Larenas-Linnemann et al., 2013) concluded that food OIT was more promising than SLIT, but few studies were included. A 2014 meta-analysis (Nurmatov et al., 2014a) identified 21 eligible trials of OIT or SLIT to foods. The meta-analysis revealed a lower risk of reactions on treatment (risk ratio [RR]: 0.21; 95% CI: 0.12-0.38). Additionally, SPT responses significantly decreased (mean difference: –2.96 millimeters [mm]; 95% CI: –4.48 to –1.45), and allergen-specific IgG4 concentrations increased by an average of 19.9 (95% CI: 17.1-22.6) μg/ml. Safety data showed an increased risk of local oral-pharyngeal and gastrointestinal adverse reactions with treatment (RR: 1.47; 95% CI: 1.11-1.95).

__________________

⁴ Case series design studies are considered to be vulnerable to selection bias because they, for example, might draw their patients from a particular population and might not represent the wider population.

Also, a non-significant increased average risk of systemic adverse reactions occurred with treatment (RR: 1.08; 95% CI: 0.97-1.19). The authors concluded that OIT can induce immunomodulatory changes and thereby promote desensitization. However, based on limited evidence on long-term efficacy and safety, as well as cost-effectiveness, they concluded that the treatment should not currently be used outside of experimental conditions.

Overall, these reviews and meta-analyses are in agreement with the guidelines noted above. However, OIT is being used clinically by a number of practice settings with various motivations (Greenhawt and Vickery, 2015; Pajno et al., 2014). Phase 3 studies are currently under way for OIT and EPIT. Numerous other approaches have been tried or are in development, such as a panoply of biologics, immune adjuvants, modified protein vaccines, traditional Chinese medicine practices, probiotics, and many others (Bauer et al., 2015; Keet and Wood, 2014; Kumar et al., 2013; Le and Burks, 2014; Nermes et al., 2013; Nowak-Wegrzyn and Sampson, 2011; Oyoshi et al., 2014; Sato et al., 2014; Senti and Kundig, 2016). Clearly, many strategies can be pursued to address treatment of food allergy.

OVERALL CONCLUSIONS

Management in the health care setting involves education about the daily strategies that patients need to follow to avoid allergen ingestion and to recognize and treat reactions promptly. Although these management approaches begin in the health care setting, success often requires involvement at the community level (see Chapter 8). Allergen avoidance, usually strict avoidance even of trace amounts of allergen, is the primary means of management. This requires significant education and caution throughout the day. In addition, it relies upon others in the community to provide safety, seriously affects quality of life, and increases anxiety. Counseling about avoidance involves emphasizing key concerns, such as cross-contact and hidden ingredients and discussing foods related to the diagnosed allergens, which may need to be avoided upon a full food allergy evaluation. Counseling is directed to managing food allergies at home, reading labels (and knowing about products that are not included in mandatory labeling laws), asking questions when eating in restaurants and during travel, and, for children, avoiding food allergens when away from home (e.g., at schools, camp, or when with friends and relatives). Such counseling should address common pitfalls that have been identified in a variety of studies. However, data to be able to provide individualized risk assessments upon which to base instructions regarding avoidance and emergency management are limited. Also, limited programs exist for educating patients, caregivers, and other stakeholders, with few evidence-based programs to ensure effectiveness, and limited information exists on implementation. Adolescents

and young adults appear to be at increased risk for fatal anaphylaxis, and their risk-taking behavior has been identified as a possible cause.

Emergency management depends upon recognizing a reaction and promptly instituting therapy. Epinephrine is the primary treatment for anaphylaxis, with auto-injectors having fixed doses used for first-aid care. However, dosing of epinephrine has not been extensively studied and current auto-injectors may not provide appropriate doses for infants or individuals with obesity. Anaphylaxis is often underrecognized and undertreated. A number of risk factors have been identified for anaphylaxis, but there are no means to reliably predict severity of anaphylaxis. Medications used as primary and adjunctive therapy for anaphylaxis have not been studied. Post-anaphylaxis care includes observation in the medical setting to ensure resolution of symptoms, prescription of medications, education on avoidance and management, and possibly referral for additional testing and management. However, numerous pitfalls to these strategies have been identified.

Avoidance diets, particularly ones involving milk or multiple foods, can affect nutrition and growth and dietitian intervention is warranted. However, data on best practices are limited. Considering the significant impact of food allergy on quality of life and emotional status, information on how best to approach these issues is severely lacking. In addition, data on aspects of management for adults are sparse.

Emerging studies show promising results for desensitizing specific allergens but more information is needed about the safest and most effective approaches and how they may be individualized based on patients allergies and needs.

The committee did not wish to repeat all reasonable management recommendations that are already noted in professional guidelines, committee reports, and practice parameters. However, the committee emphasizes some key research recommendations in alignment with such reports where the study findings suggest areas of high need and frequent deficits in management.

RECOMMENDATIONS

Numerous clinical guidelines and parameters provide advice for health care providers and patients and their caregivers on diagnosing, preventing, and managing food allergy. The committee generally supports current guidelines and U.S. practice parameters for food allergy management and the committee emphasizes those areas where improvements would lead to significant changes in the quality of life of patients and their caregivers, such as training and education of the general public and all stakeholders.

Public Health Authorities, Health Care Providers, and Their Patients and Caregivers

RESEARCH NEEDS

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 non-oral allergen exposures (e.g., skin-exposure and inhalation).

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