OVERVIEW

A diagnosis of food allergy carries numerous health, emotional, social, and nutritional consequences. Therefore, a proper diagnosis is imperative. Unfortunately, studies suggest that many individuals needlessly avoid foods on the presumption of a food allergy without seeking medical confirmation, a practice that can lead to unnecessary risk and burden (Boyce et al., 2010; Fleischer et al., 2011; Rona et al., 2007). For example, in one meta-analysis, the rate of self-reported food allergy was 12 percent and 13 percent for children and adults compared to 3 percent when confirmation with testing was applied (Boyce et al., 2010; Rona et al., 2007). One of the major issues in food allergy is the common misconception that having a “positive test,” by a blood test or allergy skin prick test (SPT, otherwise known as sensitization, or a condition in which an individual produces detectable food-specific immunoglobulin E [IgE] antibody), is equivalent to having a clinical food allergy. For example, Fleischer et al. performed 111 supervised feeding tests with 44 children avoiding foods because of positive skin or serum allergy tests and, overall, 93 percent of the children were tolerant of the avoided food (Fleischer et al., 2011). Although this was a subpopulation of children with high rate of atopic dermatitis, on a population level, many more persons are also sensitized to foods than are clinically reactive upon ingestion. For example, 2005-2006 National Health and Nutrition Examination Survey (NHANES) data showed a 7.6 percent rate of positive serum IgE tests to peanut (10.7 percent in children ages 6 to 19 years), clearly higher than the prevalence of clinical peanut allergy (Liu et al., 2010). Compounding the problem, many physicians lack an understanding of how to apply common diagnostic tests and interpret the results. In a survey of 407 primary care physicians, less than 30 percent of the participants reported that they were comfortable interpreting laboratory tests to diagnose food allergy, and 38 percent indicated incorrectly that skin or blood tests were sufficient for a diagnosis (Gupta et al., 2010). Clearly, the lack of understanding among physicians is compounded among the lay public.

Although overdiagnosis is a concern, conversely, assuming that an allergen has been identified as a trigger of a serious allergic response, a lack of confirmation could lead to re-exposure to the true culprit, with serious consequences. It is therefore imperative that individuals with suspected food allergy seek a medical diagnosis to identify whether the cause of symptoms is a food allergy and to identify culprit foods.

Considering the various symptoms (e.g., rashes, respiratory symptoms, gastrointestinal [GI] symptoms) and medical illnesses (e.g., atopic dermatitis, anaphylaxis) attributable to food allergy, many of which have alternate diagnoses (i.e., intolerance, pharmacologic reactions), or nonfood triggers (i.e., pollen allergy, irritants), food allergy diagnosis is complicated. Additionally, no simple tests exist that, in isolation, diagnose a specific food allergy (Boyce et al., 2010; Sampson et al., 2014). The primary tools currently available for diagnosis include the medical history, elimination diets, SPT, food-specific IgE (sIgE) (serum tests for food-specific IgE against specific proteins in foods), component resolved diagnostics (CRD), and medically supervised oral food challenges (OFCs).

This chapter includes relevant aspects of mechanisms of food allergy in relation to the current accepted methods for diagnostic testing and prognosis, including misconceptions about the methods, limitations, and factors that might affect diagnosis. The chapter also describes some promising methods that need further research, validation, or standardization before being used routinely, and methods that are not recommended for use routinely. The chapter ends with overall conclusions, recommendations, and research needs.

APPROACH TO LITERATURE REVIEW

In preparing this chapter, new individual systematic reviews or meta-analyses were not conducted. The primary resources for discussion, findings, conclusions, and recommendations were derived from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH)–supported Guidelines (Boyce et al., 2010), the European Academy of Allergy & Clinical Immunology (EAACI) Guidelines (Muraro et al., 2014), and associated systematic reviews (Soares-Weiser et al., 2014) as well as the American Academy of Allergy, Asthma & Immunology (AAAAI) Guidelines (Sampson et al., 2014; see Chapter 1, Table 1-1). Additional PubMed searches were selectively performed to identify studies and reports in the literature, especially focusing on papers published after the aforementioned reports. Meta-analyses, systematic reviews, expert reports, and practice guidelines were selected when available and supplemented with more recent publications.

REASONS TO INITIATE ASSESSMENTS FOR FOOD ALLERGY

The NIAID/NIH-supported Guidelines (Boyce et al., 2010) suggest that food allergy should be considered in a number of specific circumstances. Having allergic symptoms within minutes to hours after ingestion, especially from a specific food on more than one occasion, is suggestive of a food allergy and warrants investigation. Symptoms can include skin symptoms of itchy rashes, hives, or swelling; eye symptoms of itching, tearing, redness, or swelling; oral symptoms of itching or swelling of the lips, tongue, or palate; upper airway symptoms of congestion, itching, sneezing, nasal discharge, or hoarseness; lower airway symptoms of cough, chest tightness, wheezing, or trouble breathing; gastrointestinal symptoms of nausea, pain, vomiting, or diarrhea; cardiovascular symptoms of fast or slow heart rate, dizziness, low blood pressure, confusion, loss of consciousness; uterine contractions; and a sense of “impending doom.”

Food allergy diagnostic testing also may be warranted for infants, young children, and selected older individuals with moderate to severe atopic dermatitis because a higher rate of food allergy occurs in these populations, whether or not the food allergy may be contributing to the rash (Boyce et al., 2010; Sidbury et al., 2014). Disorders with subacute or chronic symptoms that indicate food-related disorders, such as food protein–induced enterocolitis (FPIES), enteropathy, and allergic colitis, also warrant investigation for food-allergic triggers. Food allergy also should be considered in children and adults with eosinophilic esophagitis (Boyce et al., 2010; Liacouras et al., 2011; Markowitz et al., 2003). Importantly, food allergy is not a typical trigger of chronic asthma or chronic rhinitis in childhood (Boyce et al., 2010; Sampson et al., 2014), although it can cause occupational asthma in certain groups, such as bakers or shellfish handlers.

The initiation of food allergy diagnostic testing also has some areas of uncertainty. For example, one expert panel (Boyce et al., 2010) concluded that there was insufficient evidence to recommend routine food allergy testing before introducing highly allergenic foods to children at high risk of food allergy, such as those with pre-existing severe allergic disease or family history of food allergy. However, they indicated value in such evaluations for selected patients, such as those having a peanut allergy or evidence of another underlying food allergy. For example, testing for tree nut allergy in a child with peanut allergy who has not yet been exposed to tree nuts would be appropriate. Similarly, consensus recommendations regarding introduction of peanut to high-risk infants with early-onset atopic disease, such as severe eczema or egg allergy, have suggested that infants might benefit from evaluation to diagnose any food allergy and to evaluate an infant for introduction of peanut (Fleischer et al., 2015).

A common misconception or concern among caregivers is that if one sibling develops a food allergy, other siblings also will become allergic. However, a recent study of a large cohort of families with food allergies found that only a small proportion of siblings are both sensitized (based on SPT and IgE) and clinically reactive to a food (based on history of typical symptoms of an allergic reaction to a food) (Gupta el al., 2016). In support of NIAID/NIH-supported Guidelines (Boyce et al., 2010), the authors concluded that testing for food allergy in siblings without a history of clinical reactivity appears to be unjustified and that screening may lead to negative consequences related to potential misdiagnosis and unnecessary avoidance of a food.

MECHANISMS OF FOOD ALLERGY IN RELATIONSHIP TO DIAGNOSTIC TESTING

Chapter 2 described specific food allergic disorders and pathophysiology. With regard to diagnostic testing, the pathophysiology of the disorder is relevant. For example, tests for food-specific IgE antibodies (i.e., SPT, sIgE, and CRD) are relevant for IgE-mediated disorders. These tests may sometimes be performed in disorders that are non-IgE-mediated to identify a potential for acute allergic reactions if the previously consumed food has been removed from the diet after having been a part of the diet (Liacouras et al., 2011), or to determine whether there has been a change in pathophysiology to an IgE-mediated disorder, as can occur with FPIES (Caubet et al., 2014). In contrast, the medical history, elimination diets, and physician-supervised OFCs are useful in all food allergic disorder evaluations.

CURRENTLY AVAILABLE MODALITIES ROUTINELY USED TO DIAGNOSE FOOD ALLERGY

A number of modalities have been recommended for diagnosing food allergy (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). These are reviewed briefly in the following section with an emphasis on utility and limitations. The diagnostic tests discussed below are generally not used in isolation (see “General Diagnostic Algorithms”).

Food-Specific Serum IgE

Guidelines recommend using sIgE tests to identify foods that may provoke IgE-mediated reactions, but the test result alone is not considered sufficient for diagnosis (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). The choice of tests is guided by the clinical history. Modern tests use fluorescence enzyme-labeled assays and have replaced radioallergosorbent tests (RAST). The term “RAST” is therefore antiquated. In the United States, the Food and Drug Administration (FDA) has approved three automated systems to measure sIgE. Each system has slightly different methods for test development, and results from one system are not directly comparable to others (Hamilton and Williams, 2010; Hamilton et al., 2011; Wang et al., 2008). sIgE is not affected by antihistamine use, as SPTs are.

TABLE 4-1

Sensitivity and Specificity of SPT for Selected Foods.

The sensitivity and specificity of SPT and sIgE were evaluated in a 2010 meta-analysis with a conclusion that neither test was statistically superior (Chafen et al., 2010). However, SPTs and sIgE tests do not always correlate, and so doing both tests can be advantageous, as can doing one followed by the other, if clinically warranted. A 2014 systematic review and meta-analysis (Soares-Weiser et al., 2014) considered mixed cut-off levels for sIgE but chose a >0.35 kU_A/L² value when possible. The sensitivities and specificities for various allergenic food are in Table 4-2.

Laboratory reports of undetectable sIgE concentrations occasionally occur in patients who go on to react to the food tested probably for reasons similar to the ones described above for SPT, so caution and additional evaluation is necessary in this circumstance if a history is highly suggestive of food allergy. In addition, different laboratories or test systems may report test results at different detection limits, for example <0.10 or <0.35 kU_A/L.

Studies have correlated increasing sIgE levels with increasing risk of clinical allergy. Some studies have calculated cut-off levels suggesting 95 percent predictive values for clinical reactivity (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). Although 95 percent predictive cutoff values have been calculated in specific studies, these values vary between studies, likely due to differences in patient selection, age, clinical disorders evaluated, and many other factors. The predictive values of certain cut-offs are dependent on the frequency of the food allergy and may therefore differ widely in different populations.

TABLE 4-2

Sensitivity and Specificity of Food-Specific Serum IgE (sIgE) Test for Selected Foods.

MODALITIES NOT RECOMMENDED FOR ROUTINE USE

NONSTANDARDIZED AND UNPROVEN PROCEDURES

A number of tests have been referred to as “unproven,” “unconventional,” or “nonstandardized and unproven” by guidelines and are not recommended for food allergy diagnosis (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). These tests or procedures include: allergen-specific IgA, IgG or IgG₄, provocation neutralization, immune complexes, HLA screening, lymphocyte stimulation, facial thermography, gastric juice analysis, endoscopic allergen provocation, hair analysis, applied kinesiology, cytotoxic assays, electrodermal testing, mediator release assays, bio-resonance, and iridology. The rationale for not recommending these tests or procedures is the lack of evidence demonstrating the value of each method in diagnosis of food allergy. There is a concern that use of these methods may result in false positive or false negative diagnoses that may lead to unnecessary dietary restriction or may delay appropriate diagnostic evaluations.

For example, IgG₄ testing against foods as a diagnostic modality was reviewed in the 2008 EAACI Task Force report (Stapel et al., 2008). Many serum samples have positive IgG₄ results without corresponding clinical symptoms. The report noted a lack of convincing evidence for histamine-releasing properties of IgG₄, and a lack of controlled studies to determine diagnostic value. Conversely, evidence suggests that food-specific IgG₄ reflects exposure, and may indicate a state of immunological tolerance. The task force concluded that testing of IgG₄ to foods is irrelevant to the laboratory work-up for diagnosis of food allergy. It should be noted, however, that food-specific IgG and IgG₄ responses, when monitored during immune therapy with allergen exposure, is associated with clinical improvement in threshold. Thus, IgG and IgG₄ may be markers or mechanisms of desensitization and may have some role in diagnosis, especially during treatments, when considered along with other measurements, such as sIgE. Studies have begun to evaluate the diagnostic or prognostic potential of the IgE/IgG ratio or antibody classes. More studies are needed to validate these approaches, as currently available data are conflicting (Ahrens et al., 2010; Caubet et al., 2012; Dannaeus and Inganas, 1981; Okamoto et al., 2012; Savilahti et al., 2012, 2014; Sverremark-Ekström et al., 2012; Tomicic et al., 2009).

PREDICTION OF SEVERITY OR THRESHOLD OF REACTIONS

Severity of an allergy is typically defined by symptoms triggered during an allergic reaction, and threshold of exposure for a reaction refers to the dose of allergen that triggers symptoms. There is strong interest in, and need for, a test for severity or threshold. Dosing during OFC is generally stopped before severe symptoms, limiting the ability of this study design to predict severe reactions (Wainstein et al., 2010). No comprehensive reviews have been published on the prediction of severity or on simple tests to diagnose the severity of a reaction. One might surmise that increasing sIgE concentrations correlate with severity because they correlate with risk of clinical reactivity. Although a number of studies suggest this correlation, it has not been universally substantiated (Benhamou et al., 2008; Blumchen et al., 2014; Clark and Ewan, 2003; Neuman-Sunshine et al., 2012; Rolinck-Werninghaus et al., 2012; Summers et al., 2008; Ta et al., 2011; van der Zee et al., 2011; Wainstein et al., 2010). In addition, CRD could be considered a means to possibly diagnose severity of a reaction because, for example, isolated binding to Ara h 8 is associated with no or mild allergy (oral-pharyngeal symptoms, related to PFAS) while binding to Ara h 2 is associated with systemic peanut allergy. However, on an individual patient or research study participant basis, degree of binding to Ara h 2 does not appear to accurately predict severity (Astier et al., 2006; Klemans et al., 2013a,b; Leo et al., 2015; Peeters et al., 2007). Studies have suggested that modalities such as BAT (Homsak et al., 2013; Santos et al., 2015; Song et al., 2015) or analysis of epitope³ binding patterns (Flinterman et al., 2008; Shreffler et al., 2004) may hold promise for determining severity. Disparities in prediction of severity based on testing may have many methodological reasons, but on an individual basis, outside of studies that control for such variables, the tests may not or do not currently consider specific patient-circumstance variables, such as whether the individual with food allergy has asthma, is currently ill, exercising, or experiencing other factors that may cause increased sensitivity (i.e., eliciting factors, other factors regarding physiologic responses) (Summers et al., 2008; Vadas et al., 2008). A recent paper describes the lack of predictability, perceptions about severity, and the types of factors that may affect the severity of a reaction, including those related to a person's behaviors (e.g., exercise) and other factors (e.g., infections) (Turner et al., 2016).

PROGNOSIS AND DISEASE MONITORING

The rate of allergy resolution varies based on the food, patient's age, pathophysiology of the allergy, and other factors (Boyce et al., 2010; Sampson et al., 2014). Table 4-3 summarizes resolution rates of common food allergies (Savage et al., 2016). Most children with allergies to cow milk, egg, soy, and wheat will develop tolerance by adulthood, whereas resolution of peanut, tree nut, and seafood allergies is less likely (less than or equal to 20 percent) (Boyce et al., 2010; Sampson et al., 2014). Adults with food allergies may have experienced persistence from childhood or may have a new onset in adulthood, and these allergies tend to persist. The natural course of food allergy is not known for most foods. Periodic re-evaluation with testing is recommended and can be individualized based on patient characteristics, the food, and underlying food allergic disorder (Boyce et al., 2010; Sampson et al., 2014). In general, periodic re-evaluation is undertaken with history, SPT, sIgE, and OFC depending on the specific results of each test and history. This testing might be performed more frequently (e.g., yearly) for a young child with food allergies, and less frequently (e.g., every few years) for an adult with allergies to foods such as peanut, tree nuts, and seafood.

Unfortunately, no simple accurate prognostic tests exist. Having tests that could be performed early in life that reflect prognosis would be helpful in selecting the best periodicity of retesting, providing anticipatory guidance, and identifying which patients might benefit from interventional treatments (as these become available). Studies have suggested that higher compared to lower concentrations of sIgE or skin test size are a poor prognostic marker (Ho et al., 2008; Keet et al., 2009; Peters et al., 2013, 2015; Savage et al., 2007, 2010; Sicherer et al., 2014; Skripak et al., 2007; Wood et al., 2013). However, additional clinical factors are associated with prognosis, including severity of symptoms, threshold dose, family history, change in sIgE over time, ability to tolerate milk or egg in baked goods (for cow milk and egg allergy), comorbid asthma, and comorbid atopic dermatitis (including severity), and other factors (Cantani and Micera, 2004; Elizur et al., 2012; Ho et al., 2008; Peters et al., 2013, 2014, 2015; Savage et al., 2007; Shek et al., 2004; Sicherer et al., 2014; Skripak et al., 2007; Wood et al., 2013). Studies have used multivariate analysis to create predictive models using the variables with the greatest impact (especially sIgE levels), but validation is needed (Sicherer et al., 2014; Wood et al., 2013). Studies using newer in vitro tests, such as CRD and BAT, have not been extensively applied to develop prognostic algorithms. A 2013 systematic search and review on this topic identified 26 articles, noting heterogeneity and biases in the studies, and concluded that population-based, prospective studies are needed that use OFC—without bias of test results—to diagnose food allergy at baseline and then to follow up to develop thresholds for SPT and sIgE that predict the course of food allergy (Peters et al., 2013). Little is known about food allergy prognosis after diagnosis in adulthood.

TABLE 4-3

Natural Course of Food Allergy.

Many of the modalities discussed here also have been evaluated during treatment studies, to identify markers that may indicate desensitization or tolerance of food(s) to which individuals are initially allergic, including sIgE, SPT, CRD, BAT, sIgE/total IgE ratio, sIgG₄, and ratio of sIgE to sIgG₄ (Nozawa et al., 2014; Savilahti et al., 2014; Thyagarajan et al., 2012; Vickery et al., 2013, 2014). Additional markers have been followed, including cytokines, regulatory T cells, T cell number and function, and B cell activity (Bedoret et al., 2012; Hoh et al., 2016; Syed et al., 2014; Varshney et al., 2011). However, biomarkers to confirm desensitization and tolerance without OFC remain to be found.

GENERAL DIAGNOSTIC ALGORITHMS

Guidelines and reviews have suggested general algorithms (i.e., panels) for diagnostic approaches (Greenhawt et al., 2013; Muraro et al., 2014; Sicherer, 2002; Urisu et al., 2014; Venter et al., 2013). Approaches typically begin with a medical history to identify the nature of the symptoms (whether likely reflecting food allergy or another disorder), the pathophysiology (IgE mediated or not), and the potential food triggers. Testing based on the initial impressions is conducted and interpreted based on the results of the history and suspected foods and related pathophysiology. This may include tests for IgE, elimination diets and/or OFCs, depending on the circumstances.

Different algorithms may fit specific disorders. For example, evaluation of food allergy in acute anaphylaxis, where symptoms come on quickly and are associated with sIgE antibodies, differs from evaluation of the role of food allergy in atopic dermatitis or EoE (Greenhawt et al., 2013; Sicherer, 2002; Urisu et al., 2014; Venter et al., 2013). No overarching approach has been universally accepted. However, because the sensitivity and specificity of individual tests are generally not 100 percent, using pretest probability obtained from one test (e.g., the medical history) is recognized as beneficial for interpreting the post-test probability of allergy following a second test (Muraro et al., 2014). Indiscriminately performing multiple tests is not recommended (Boyce et al., 2010), but a case can be made for using more than one test when additional diagnostic value may be obtained. Specific algorithms may, for example, consider diagnostic values of several tests performed in series to improve accuracy (Ben-Shoshan et al., 2010; Dang et al., 2012). Additionally, it may be possible to isolate a number of factors from the medical history and simple diagnostic tests to estimate the risk of an allergy, using a standardized approach, but this also needs validation (DunnGalvin et al., 2011). In summary, although no evidence-based, universally accepted overarching diagnostic algorithm exists, guidelines promote step-wise evaluations rather than solely depending upon single tests to conclude a diagnosis of food allergy in children (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). Information on adults is limited.

TESTING FOR SPECIFIC DISEASE STATES OTHER THAN ANAPHYLAXIS AND ATOPIC DERMATITIS

As indicated above, diagnostic approaches may vary depending upon the pathophysiology, epidemiology, and clinical characteristics of particular food-allergic disorders (Greenhawt et al., 2013; Muraro et al., 2014; Sicherer, 2002; Urisu et al., 2014; Venter et al., 2013).

COMMON PITFALLS AND MISCONCEPTIONS IN DIAGNOSTICS

As indicated previously, diagnostic and monitoring tests have a variety of limitations that, if not appreciated, can result in over- or underdiagnosing food allergy in patients. Table 4-4 summarizes common misconceptions.

Clinically Relevant and Nonrelevant Cross Reactivity

Another potential pitfall is recognizing the difference between cross reactivity identified on testing (sIgE or SPT) that may or may not be clinically relevant (Sampson et al., 2014; Sicherer, 2001). When food allergens share sufficient homology, antibodies may be detected to multiple allergen proteins, but the clinical relevance of the test finding can vary. For example, a large proportion of individuals with peanut allergy will test positive to other legumes, such as soy (up to 79 percent), but only a small proportion of patients (up to 5 percent) will experience allergic reactions to them. Although the test rate of cross reactivity is higher than the observed rate of clinical cross reactivity, studies on this topic are limited and likely reflect results that vary depending upon methodology, patient selection, and geographic influences, including pollen sensitization. Estimated rates of clinical cross reactivity among crustacean shellfish is 38 percent, among fish 30 to 75 percent, among tree nuts 12 to 37 percent (varies depending on the nuts; for example, walnut and pecan are more similar, cashew and pistachio are more similar), and between wheat and other grains 21 percent. An OFC is often needed to confirm tolerance if a potentially cross reactive food has not already been tolerated in the diet. A serious pitfall can occur if a food tests positive in panels (and the patient removes it from the diet) when tolerance has already been proven by inclusion of the food in the diet.

TABLE 4-4

Common Misconceptions About Food Allergy and Testing.

ROLE OF ELICITING FACTORS

Eliciting factors, also referred to as cofactors and augmentation factors, are circumstances or ingestants that can alter threshold or severity of an allergy, resulting in more serious reactions or allowing clinical expression of a food allergic response to an otherwise tolerated food (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). These factors can include exercise, nonsteroidal anti-inflammatory drug (NSAID) agents, alcohol, body temperature, menstruation, infections, stress, and antacid medications (Niggemann and Beyer, 2014). These factors may influence absorption or immune responses. The best described entity is food-associated (dependent), exercise-induced anaphylaxis, where the food is tolerated when exercise does not occur, but reactions may occur when the food is ingested before exercise. Common food allergenic foods that trigger a reaction with exercise are wheat, shrimp, and celery, but numerous triggers have been reported (Romano et al., 2001).

The possibility that a cofactor is responsible for the expression of a food allergy is assessed by history, and assessment may include evaluation by SPT or sIgE of foods ingested before exercise or concomitant ingestion of alcohol or NSAIDs. A case can be made for evaluating specific allergens associated with these syndromes, such as gliadin and lipid transfer proteins in some settings, but the diagnostic utility is not fully understood (Muraro et al., 2014; Romano et al., 2012; Urisu et al., 2014). The history and supporting test evidence may warrant the diagnosis, but OFC with exposure to the eliciting factor may be needed. The reliability of such testing is variable, and the symptoms can recur despite an OFC not triggering reactions. Many factors may confuse the diagnostic approach, such as the need for multiple different or a combination of augmenting factors to result in a reaction, various degrees of the factor (amount of food, exercise, alcohol), and testing methodology (Asaumi et al., 2016; Brockow et al., 2015; Jo et al., 2012; Medrala et al., 2014; Niggemann and Beyer, 2014).

FUTURE DIAGNOSTIC MODALITIES

Food allergy guidelines have recognized a large number of approaches under investigation to improve diagnosis and provide insights on prognosis and severity (Boyce et al., 2010; Muraro et al., 2014; Sampson et al., 2014). Many of these approaches have been reviewed above (CRD, BAT, and others). The diagnostic value of determining the pattern of IgE binding to synthetic sequential epitopes (binding segments) of allergens has been evaluated, with results suggesting that this testing can provide information on phenotype (i.e., ability to tolerate extensively heated milk in those with cow milk allergy), prognosis, and severity (e.g., diversity of binding associated with severity of reactions) (Cerecedo et al., 2008; Flinterman et al., 2008; Jarvinen et al, 2001, 2002; Lin et al., 2012; Shreffler et al., 2004; Wang et al., 2010).

As reviewed above, a number of cellular markers are being evaluated to improve diagnosis and prognosis, including cytokines, regulatory T cells, T cell number and function, B cell activity, and epitope binding (Bedoret et al., 2012; Hoh et al., 2016; Syed et al., 2014; Varshney et al., 2011). One study suggests value in determining deoxyribonucleic acid (DNA) methylation signatures (Martino et al., 2015). Martino et al. performed genome-wide DNA methylation profiling on subjects who had undergone OFC, concurrent SPTs, and specific IgE tests (Martino et al., 2015). Fifty-eight were food-sensitized patients (ages 11 to 15 months), half of whom were clinically reactive, and 13 were nonallergic control subjects. Reproducibility was assessed in another 48 samples from an independent population of patients with food allergy. This study revealed a methylation signature consisting of 96 CpG sites that predict clinical outcomes. This methylation signature was superior to allergen-specific IgE and SPTs for predicting OFC outcomes. Therefore, in addition to elucidating mechanisms involved in the epigenetic regulation of food allergies and the interplay between genetic and environment, this evidence can be used to develop novel, practical, and improved diagnostic assays. Bioinformatics approaches that take into consideration multiple variables should support improved diagnostics (Lin et al., 2012). These approaches, which could include data from numerous biologic markers such as genomic, transcriptomic, proteomic, metabolomics, microbiome, and various laboratory tests, will allow for assessment of billions of variables (Chen et al., 2012).

OVERALL CONCLUSIONS

Currently, no simple diagnostic tests exist for food allergy. Selection and interpretation of tests depend on the disorder being considered (epidemiology, pathophysiology) and the individual medical history. A common pitfall in diagnosis results from performing tests for sIgE without considering the medical history, resulting in unnecessary avoidance or removal of tolerated foods from the diet (a positive test alone may not indicate a clinical allergy). The gold standard test, the OFC, carries risk and expense, and is underused. The history and available test results can often suggest a likelihood of a food allergy, presenting a reasonable pretest probability for deciding upon the need for an OFC. Understanding how the size of skin tests, concentration of sIgE, and the clinical history can provide pretest probability estimations for providing a diagnosis at this point or proceeding to other tests, including the OFC is key. CRD is currently providing improved diagnosis in some circumstances. Developing “calculators” that evaluate these currently available parameters is promising. The BAT shows promising preliminary data, but validation and commercialization are needed. Sorely missing are simple tests that would indicate, for an individual with current possible allergy symptoms, degree of severity or threshold or both, as well as prognosis.

As reviewed in the discussion above, food allergy testing strategies (history, diagnostic elimination diet, OFC, SPT, sIgE, CRD, APT) are generally not well standardized, including the various factors involved with the history, elimination diets, and food challenge. Many methodologic issues are involved in evaluating test utility, and comparisons of diagnostic utility of specific tests among different populations often show some level of disparity. Regarding SPTs, extracts are not uniformly standardized and the individual allergenic protein content may vary (Hefle et al., 1995). The FDA has approved three automated systems to determine sIgE. Each system uses slightly different methods and results from one system are not directly comparable to others (Hamilton and Williams, 2010; Hamilton et al., 2011; Wang et al., 2008). The manner of reporting SPT skin test sizes varies (e.g., reporting greatest wheal diameter, mean wheal diameter, size in relation to controls), as does the representation of sIgE levels from serum tests (e.g., classes versus concentration, kU_A/L). Different OFC regimens have been proposed in the literature as well as different means to report results. Attention to these issues affects research approaches as well as clinical care. Studies are under way to improve standardization.

Additional standardization and validation would require extensive study in different patient populations (e.g., ages, illnesses, geographic regions) and consideration of the role of eliciting factors, and circumstances where interventions are being applied to the patient (immunotherapeutic strategies as they become available). This is similarly the case for emerging diagnostics, such as epitope analysis.

Education is needed for patients and physicians to understand the meaning and limitations of commonly used food allergy test results, to know about unconventional and unproven tests, and to understand how to effectively use existing tests (or when to refer from primary care to specialist care). No comprehensive studies on the cost effectiveness of testing and misdiagnosis have been conducted. Studies on diagnostics have been primarily focused on children, and more studies of adults or comparison of adults and children are needed. Numerous potential diagnostic tests are in development. At this point, they are labor-intensive or expensive, but they may identify novel factors of use in the future.

RECOMMENDATIONS

The committee recommends that physicians use evidence-based, standardized procedures as the basis for food allergy diagnosis and avoid nonstandardized and unproven procedures (e.g., applied kinesiology, immunoglobulin G panels, electrodermal testing). When food allergy is suspected, a patient should be evaluated by a physician who has the training and experience to select and interpret appropriate diagnostic tests.

Although this process often may include an initial evaluation by a primary physician, it is important that those with suspected food allergy be diagnosed appropriately, which is likely to involve referral to or consultation with a physician specialist who can diagnose, comprehensively evaluate, and manage the food allergy.

Food allergy evaluation procedures include a medical history and physical examination, and also may include food-specific skin prick test, food-specific serum immunoglobulin E test, diagnostic food elimination diet, and oral food challenge (OFC). Selection of the specific tests needs to be individualized based on the medical history of each patient. Health care providers trained in food allergy, leaders of health care facilities, and health care payor groups can facilitate the appropriate use of OFCs, including personnel, facilities, and safety guards, so that physicians are not deterred from performing the types of diagnostic testing that are appropriate for the patient's diagnosis and care.

RESEARCH NEEDS

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 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 (sIgE antibody tests or SPT) 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 sIgE test and SPT, actually diagnose sensitization, not food allergy. A variety of diagnostic tests, such as CRD, 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, co-morbidities, 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, and
  • Diagnosing food allergy in individuals and populations (e.g., for collecting data on prevalence).

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