Elsevier

Nutrition

Volume 27, Issue 10, October 2011, Pages 983-987
Nutrition

Review
The optimal diagnostic workup for children with suspected food allergy

https://doi.org/10.1016/j.nut.2011.07.006Get rights and content

Abstract

Food allergy is defined as an abnormal immunologic reaction to food proteins that causes an adverse clinical reaction. In addition to well-known acute allergic reactions and anaphylaxis triggered by immunoglobulin E antibody–mediated immune responses to food proteins, there is an increasing recognition of cell-mediated disorders such as eosinophilic esophagitis and food protein–induced enterocolitis syndrome. More than 90% of food allergies in childhood are caused by eight foods: cow’s milk, hen’s egg, soy, peanuts, tree nuts, wheat, fish, and shellfish. The diagnostic workup for a child with suspected food allergy includes a detailed medical history, physical examination, food allergy screening tests, and responses to an elimination diet and an oral food challenge. None of the screening tests, alone or in combination, can definitely diagnose or exclude a food allergy. Novel diagnostic methods including those that focus on immune responses to specific food proteins or epitopes of specific proteins are under active study. Unconventional diagnostic methods are increasingly used, but they lack scientific rationale, standardization, and reproducibility. In selected cases, such as eosinophilic esophageal gastroenteropathies or food protein–induced gastroesophageal reflux disease, invasive procedures are mandatory for an accurate diagnosis. Properly done, an oral food challenge is still the gold standard in the diagnostic workup. An incorrect diagnosis is likely to result in unnecessary dietary restrictions, which, if prolonged, may adversely affect the child’s nutritional status and growth.

Introduction

Food allergy (FA) is a major health issue in Western societies, where some evidence has suggested that the prevalence of the disorder in childhood has increased in recent years [1]. It has been recently reported that, during the past decade in the United States, pediatric FA rates have increased by 18%, but the investigators underlined that they could not determine if these findings were related to increased awareness, reporting, and use of specific medical diagnostic codes for FA or represented a real increase of the disease [2]. A correct diagnosis of FA is important to accurately establish the prevalence and incidence of this condition and to ensure appropriate patient care. In fact, FA may have deleterious effects on family economics, social interactions, school and work attendance, and health-related quality of life. The diagnostic workup in a child with FA includes many steps, but the essential criteria are a thorough medical history and physical examination with a clear response to an oral food challenge (OFC) [3]. Although any food can provoke a reaction, relatively few foods are responsible for the vast majority of significant food-induced allergic reactions in children: cow’s milk, hen’s egg, soy, wheat, fish, peanuts, and shellfish [4], [5]. There is an increase in the prevalence of new food allergens such as sesame and kiwi [6]. Features common to major food allergens are that they are water-soluble glycoproteins ranging from 10 to 70 kDa in size and are relatively stable to heat, acid, and proteases [7].

The FA symptoms are induced through an immunologic mechanism after the ingestion of a particular food. Although FA may be associated with other forms of allergic diseases, not all patients with eczema or respiratory allergies require an evaluation for FA as a trigger of their allergic disease. In fact, only a very small proportion of patients with allergic respiratory problems, such as rhinitis and asthma, and fewer than 40% of young children with severe atopic eczema have associated FA [8]. In addressing possible food-induced allergic disease, the clinician must consider a variety of conditions that are not FA. The differential diagnosis can be particularly difficult in a child with gastrointestinal symptoms (Table 1). Adverse reactions that are not classified as FA include host-specific metabolic disorders (e.g., lactose intolerance or galactosemia), a response to a pharmacologically active component (e.g., triggered by tyramine in aged cheeses), or toxins (e.g., food poisoning). In addition, psychologic (food aversion and anorexia nervosa) or neurologic (e.g., gustatory rhinorrhea from hot or spicy foods) responses can mimic FA [9]. The wide variety of “true” clinical manifestations of FA depend on the mechanism involved in the reaction (immediate/immunoglobulin E [IgE]-mediated or delayed/non–IgE-mediated or mixed), target organ responses, and characteristics of triggering proteins [10]. Proteins that are easily degraded by heat and digestion, including many of the proteins in fruits, are unlikely to trigger severe reactions. In contrast, stable proteins, such as seed storage proteins in nuts, are more likely to trigger systemic allergic reactions [11]. Interestingly, FA could be at least in part genetically determined. Although specific genes have not been identified, peanut allergy, for example, is about 10-fold more likely to occur in a child with a sibling who is allergic to peanuts compared with the risk in the general population [12]. Recent evidence has suggested potential environmental influences on immune function favoring allergic responses, including decreased exposures to infections, an increased consumption of ω-6 and a decreased consumption of ω-3 polyunsaturated fatty acids, decreased dietary antioxidants, and an excess or a deficiency of vitamin D [13]. In children, the skin and gastrointestinal tract are the most common target organs followed by the respiratory tract, and multiple systems can be involved with rapid progression to systemic anaphylaxis. Food-induced eosinophilic esophagitis in young children is becoming more recognized by pediatricians. Table 2 presents the more common food-induced allergic disorders.

The evaluation of a child with suspected FA includes an in-depth patient history, a physical examination, screening tests, and responses to an elimination diet and an OFC (Fig. 1). In children with multiple FAs, the response to the elimination of single antigens is incomplete, and a lengthy assessment with a very restricted diet is often required. The physician should obtain a detailed patient history focused on the kind and intake of symptom-inducing foods, the time gap from food ingestion to the onset of symptoms, reproducibility, the presence or absence of any other symptom-inducing conditions, and the time of the last symptom. Timing of the first and last occurrences can reveal whether sensitivity is increasing or waning. Immediate reactions, occurring within minutes to 2 h, typically involve IgE-mediated mechanisms. Conversely, delayed reactions occur within several hours to a few days and are thought to typically involve cellular mechanisms. These considerations and the quantity necessary to trigger a reaction are helpful for planning the best procedures to explore the presence of sensitization to particular foods and to perform an OFC. Occasionally, the history can be complicated by the fact that trace amounts of foods may occur in certain products. In general, the history can be more helpful in IgE-mediated disorders, because these reactions occur so soon after food ingestion and because multiple target organs are affected. A history may be more difficult for some gastrointestinal manifestations of FA such as enterocolitis or eosinophilic esophagitis, where symptoms occur hours later or days later.

The measurement of food-specific IgE and atopy patch tests, which can explore cell-mediated reactions, are the most used FA screening tests in clinical practice. There is no minimum age for these tests, which can be performed in preterm and full-term infants, with useful results [9], [14]. In all cases, it is important to emphasize that none of these tests, alone or in combination, can definitely diagnose or exclude an FA. Immediate hypersensitivity skin prick tests (SPTs) examine for the presence of food protein-specific IgE. In general, SPTs have a sensitivity of approximately 90% but a specificity of approximately only 50% [15]. The larger the wheal from an SPT, the more likely a patient will react to the food (Table 3) [15], [16], [17]. The size of the wheal or flare from an SPT does not predict the severity of the reaction. Furthermore, the age of the patient, previous exposure/reactions to the food, and the type of food change the predictive value for a wheal size. In general, the younger the age, the smaller the skin test needs to be to have a positive predictive value; a negative skin test for IgE-mediated problems is very helpful because false-negative reactions are rare. An alternative method to detect food protein-specific IgE is by in vitro methods. Physicians may prefer to use in vitro testing when there is severe eczema, persistent dermatographism, or when it is difficult to discontinue antihistamine drugs. Similar to an SPT, a “cutoff” value can be developed for predicting 95% or even 50% predictive values using OFCs [18]. However, similar to an SPT, the predictive values change for the food, age of the patient, or the history of a previous reaction. Predictive values can be developed only for selected foods (Table 3). The younger patients have a lower cutoff value for a 95% predictive value, whereas no previous exposure to the food or a clear history has a higher predictive value.

For non–IgE-mediated disorders, fewer diagnostic tools exist. Atopy patch tests have been used for different gastrointestinal conditions related to FA and atopic dermatitis. In particular, the importance of this diagnostic procedure has been underlined in patients with eosinophilic esophagitis [19]. The negative predictive value is close to 90% except for milk, where it is close to 60%. Therefore, an atopy patch test can provide guidance but is not absolute for dietary advice for non–IgE-mediated FA. Some cellular tests, i.e., tests determining the reactivity of blood cells in vitro, have also been available (e.g., determination of histamine release, basophil degranulation, determination of sulfide leukotrienes produced by interleukin-3–primed basophils stimulated by allergens in vitro, and flow cytometric basophil activation test). The low diagnostic accuracy and lack of standardization limit acceptable use in clinical practice [3]. Complementary/alternative tests (e.g., bioresonance, kinesiology, leukocytotoxic test, electrodermal tests, iridology, and hair analysis) are quite popular in clinical practice, but there is no evidence of their diagnostic value [20]. There are no tests that indicate the severity or which patients are at high risk for severe allergic reaction or anaphylaxis. However, it has been demonstrated that patients with peanut anaphylaxis have increased platelet-activating factor (PAF) and decreased PAF acetylhydrolase (compared with normal controls, patients with FA, and patients with mild peanut reactions), suggesting failure of PAF acetylhydrolase to inactivate PAF contributes to anaphylaxis [21]. Protein microarrays can detect several allergenic proteins simultaneously in children with suspected FA. They also can predict the likelihood of persistence of an allergy to a particular food by identifying the nature of the epitope as IgE against some of these specific epitopes that are more likely to be associated with persistence than others. The advantages include rapidity of the assay and the minute quantities of sera required (50 μL). IgE epitope mapping has the potential to become an additional tool for the diagnosis/prognosis of FA and lead to a better understanding of the pathogenesis and tolerance induction [22].

Several procedures could be adopted in children with gastrointestinal symptoms possibly related to FA. These include endoscopy with histologic evaluation, esophageal pH monitoring, together with several non-invasive diagnostic tools, such as intestinal permeability, eosinophilic cationic protein, and fecal calprotectin measurement (Table 4) [3], [23]. Although these non-invasive markers would be convenient to detect an intestinal mucosal reaction to foods, no conclusive studies are available on the diagnostic accuracy of these tests, alone or in combination, in the approach of a child with suspected FA. Patients with allergic eosinophilic esophagitis or gastroenteritis have peripheral eosinophilia, and children with severe allergic eosinophilic gastroenteritis may have anemia, blood in the stool, and decreased serum albumin and IgG levels. Endoscopy with biopsies is the most definitive approach and might help the differential diagnoses. A density greater than 15 to 20 eosinophils/high-power field in the esophagus is diagnostic for allergic eosinophilic esophagitis, especially if the esophageal pH monitoring is normal and there is a lack of response to high-dose proton pump inhibitor medication [19]. If gastrointestinal food-induced enteropathies or colitis is suspected, intestinal biopsies disclosing primarily eosinophilic infiltration of the mucosa may be helpful. The mucosal lesions in FA enteropathies are characteristically focal. Thus, sampling error results in negative biopsies in a discrete number of cases. Colonic biopsies often are more helpful in cases with allergic colitis, usually seen in infants with FA-induced hematochezia. In children with FA, electrogastrographic evidence of severe gastric dysrhythmia and delayed gastric emptying during a food challenge has been demonstrated. The assessment of gastrointestinal motility (e.g., multichannel intraluminal electrical impedance testing, micromanometric techniques, gastrointestinal electrophysiologic studies, and measurement of gastric emptying by 13C-octanoic acid breath test) is useful to facilitate investigations of FA-related motility disorders [24].

The OFC still represents the gold standard for the diagnosis of FA to avoid unjustified diets. In cases in which the challenge food is still part of a patient’s diet, a strict elimination diet should be prescribed for at least 2 wk before the OFC. The optimal duration of an elimination diet before an OFC depends mainly on symptom severity and the particular condition related to the FA. If the patient has experienced a severe reaction recently, an OFC is not indicated before 12 mo. Different FA-related gastrointestinal diseases require different durations of an elimination diet before an OFC (Fig. 2). The OFC is done by gradually feeding increasing amounts of the suspected food under observation by a physician over hours or days. Because the procedure carries a small risk of anaphylaxis, it should be conducted in a supervised medical setting where resuscitation equipment is available. Several studies have been published recently on this topic aiming to standardize the procedure [25], [26], [27]. The main problems are related to the wide variety of symptoms possibly related to an FA that lead to difficulties in the interpretation of test results and to the optimal timing and dosage of this procedure. A double-blind, placebo-controlled food challenge, routinely used in research, is recommended in clinical settings in which patients report subjective symptoms, whereas an open OFC without placebo is commonly used in children younger than 3 y and for diagnosing objective symptoms [28], [29], [30].

Section snippets

Conclusions

A correct diagnosis of FA is crucial to ensure appropriate patient care. The essential criterion is a clear response to an elimination diet, and other diagnostic tests are secondary to this. The OFC plays a crucial role in the diagnosis of FA, but it is largely underused even by allergy specialists. Potential responsible factors contributing to the lack of a correct diagnostic workup in the vast majority of cases in our study population could be numerous and include a lack of training in the

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