ReviewThe optimal diagnostic workup for children with suspected food allergyRoberto Berni Canani M.D., Ph.D.*, Mara Di Costanzo M.D., Riccardo Troncone M.D.Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University of Naples“Federico II”, Naples, Italyarticle infoArticle history:Received 23 July 2011Accepted 23 July 2011Keywords:Skin prick testingFood-specific serum immunoglobulinIgE levelsAtopy patch testingOral food challengeGastrointestinal symptomsabstractFood allergy is defined as an abnormal immunologic reaction to food proteins that causes anadverse clinical reaction. In addition to well-known acute allergic reactions and anaphylaxistriggered by immunoglobulin E antibody–mediated immune responses to food proteins, there is anincreasing recognition of cell-mediated disorders such as eosinophilic esophagitis and foodprotein–induced enterocolitis syndrome. More than 90% of food allergies in childhood are causedby eight foods: cow’s milk, hen’s egg, soy, peanuts, tree nuts, wheat,fish, and shellfish. Thediagnostic 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 oralfood challenge. None of the screening tests, alone or in combination, can definitely diagnose orexclude a food allergy. Novel diagnostic methods including those that focus on immune responsesto specific food proteins or epitopes of specific proteins are under active study. Unconventionaldiagnostic methods are increasingly used, but they lack scientific rationale, standardization, andreproducibility. In selected cases, such as eosinophilic esophageal gastroenteropathies or foodprotein–induced gastroesophageal reflux disease, invasive procedures are mandatory for anaccurate diagnosis. Properly done, an oral food challenge is still the gold standard in the diagnosticworkup. An incorrect diagnosis is likely to result in unnecessary dietary restrictions, which, ifprolonged, may adversely affect the child’s nutritional status and growth.Ó2011 Elsevier Inc. All rights reserved.IntroductionFood allergy (FA) is a major health issue in Western societies,where some evidence has suggested that the prevalence of thedisorder in childhood has increased in recent years[1]. It hasbeen recently reported that, during the past decade in the UnitedStates, pediatric FA rates have increased by 18%, but the inves-tigators underlined that they could not determine if thesefind-ings were related to increased awareness, reporting, and use ofspecific medical diagnostic codes for FA or represented a realincrease of the disease[2]. A correct diagnosis of FA is importantto accurately establish the prevalence and incidence of thiscondition and to ensure appropriate patient care. In fact, FA mayhave 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 andphysical examination with a clear response to an oral foodchallenge (OFC)[3]. Although any food can provoke a reaction,relatively few foods are responsible for the vast majority ofsignificant food-induced allergic reactions in children: cow’smilk, hen’s egg, soy, wheat,fish, peanuts, and shellfish [4,5].There is an increase in the prevalence of new food allergens suchas sesame and kiwi[6]. Features common to major food allergensare that they are water-soluble glycoproteins ranging from 10to 70 kDa in size and are relatively stable to heat, acid, andproteases[7].Clinical characteristics useful in the diagnostic workupThe FA symptoms are induced through an immunologicmechanism after the ingestion of a particular food. Although FAmay be associated with other forms of allergic diseases, not allpatients with eczema or respiratory allergies require an evalua-tion for FA as a trigger of their allergic disease. In fact, only a verysmall proportion of patients with allergic respiratory problems,such as rhinitis and asthma, and fewer than 40% of young chil-dren with severe atopic eczema have associated FA[8].Inaddressing possible food-induced allergic disease, the clinicianmust consider a variety of conditions that are not FA. Thedifferential diagnosis can be particularly difficult in a child with*Corresponding author. Tel.:þ39-081-746-2680; fax:þ39 081-546-9811.E-mail address:berni@unina.it(R. Berni Canani).0899-9007/$ - see front matterÓ2011 Elsevier Inc. All rights reserved.doi:10.1016/j.nut.2011.07.006Contents lists available atScienceDirectNutritionjournal homepage:www.nutritionjrnl.comNutrition 27 (2011) 983–987
gastrointestinal symptoms (Table 1). Adverse reactions that arenot classified as FA include host-specific metabolic disorders(e.g., lactose intolerance or galactosemia), a response to a phar-macologically active component (e.g., triggered by tyramine inaged 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) responsescan mimic FA[9]. The wide variety of“true”clinical manifesta-tions 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 character-istics of triggering proteins[10] . Proteins that are easily degradedby heat and digestion, including many of the proteins in fruits,are unlikely to trigger severe reactions. In contrast, stableproteins, such as seed storage proteins in nuts, are more likelyto trigger systemic allergic reactions[11] . Interestingly, FA couldbe at least in part genetically determined. Although specificgenes have not been identified, peanut allergy, for example,is about 10-fold more likely to occur in a child with a sibling whois allergic to peanuts compared with the risk in the generalpopulation[12] . Recent evidence has suggested potential envi-ronmental influences on immune function favoring allergicresponses, including decreased exposures to infections, anincreased consumption ofu-6 and a decreased consumption ofu-3 polyunsaturated fatty acids, decreased dietary antioxidants,and an excess or a deficiency of vitamin D[13] . In children, theskin and gastrointestinal tract are the most common targetorgans followed by the respiratory tract, and multiple systemscan be involved with rapid progression to systemic anaphylaxis.Food-induced eosinophilic esophagitis in young children isbecoming more recognized by pediatricians.Table 2presents themore common food-induced allergic disorders.Multistep diagnostic processThe 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). Inchildren with multiple FAs, the response to the elimination ofsingle antigens is incomplete, and a lengthy assessment witha very restricted diet is often required. The physician shouldobtain a detailed patient history focused on the kind and intakeof symptom-inducing foods, the time gap from food ingestion tothe onset of symptoms, reproducibility, the presence or absenceof any other symptom-inducing conditions, and the time of thelast symptom. Timing of thefirst and last occurrences can revealwhether sensitivity is increasing or waning. Immediate reac-tions, occurring within minutes to 2 h, typically involve IgE-mediated mechanisms. Conversely, delayed reactions occurwithin several hours to a few days and are thought to typicallyinvolve cellular mechanisms. These considerations and thequantity necessary to trigger a reaction are helpful for planningthe best procedures to explore the presence of sensitization toparticular foods and to perform an OFC. Occasionally, the historycan be complicated by the fact that trace amounts of foods mayoccur in certain products. In general, the history can be morehelpful in IgE-mediated disorders, because these reactions occurso soon after food ingestion and because multiple target organsare affected. A history may be more difficult for some gastroin-testinal manifestations of FA such as enterocolitis or eosinophilicesophagitis, where symptoms occur hours later or days later.Food allergy screening testsThe measurement of food-specific IgE and atopy patch tests,which can explore cell-mediated reactions, are the most used FAscreening tests in clinical practice. There is no minimum age forthese tests, which can be performed in preterm and full-terminfants, with useful results[9,14]. In all cases, it is important toemphasize that none of these tests, alone or in combination,can definitely diagnose or exclude an FA. Immediate hypersen-sitivity skin prick tests (SPTs) examine for the presence of foodprotein-specific IgE. In general, SPTs have a sensitivity ofapproximately 90% but a specificity of approximately only 50%[15] . The larger the wheal from an SPT, the more likely a patientwill react to the food (Table 3) [15–17] . The size of the wheal orflare from an SPT does not predict the severity of the reaction.Furthermore, the age of the patient, previous exposure/reactionsto the food, and the type of food change the predictive value fora wheal size. In general, the younger the age, the smaller the skintest needs to be to have a positive predictive value; a negativeskin test for IgE-mediated problems is very helpful becausefalse-negative reactions are rare. An alternative method to detectfood protein-specific IgE is by in vitro methods. Physicians mayprefer to use in vitro testing when there is severe eczema,persistent dermatographism, or when it is difficult to dis-continue antihistamine drugs. Similar to an SPT, a“cutoff”valuecan be developed for predicting 95% or even 50% predictiveTable 1Main conditions to be considered in the differential diagnosis in the diagnosticapproach to a child with suspected food allergy–related gastrointestinalsymptomsInfectionsGastrointestinal functional disordersCeliac diseaseBrush border enzyme deficienciesCysticfibrosis and other primitive forms of pancreatic insufficiencyInflammatory bowel diseasesAnatomic defects (e.g., pyloric stenosis, malrotation)Metabolic disorders (e.g., galactosemia)Adverse reaction to drugsMunchausen’s syndrome/Munchausen’s syndrome by proxyTable 2Food-induced allergic disordersIgE-mediated/acute onsetNon–IgE-mediated/delayed onsetIgE- or non–IgE–mediated/delayed onsetGastrointestinaltractOral allergy syndrome;gastrointestinal anaphylaxisDietary protein proctitis; colitis; enterocolitis;enteropathy; gastroesophageal reflux disease;food-protein–induced enterocolitis syndrome;chronic constipation; infantile colicEosinophilic; esophagitis;gastroenteropathiesRespiratory tractRhinitis; conjunctivitis; asthmaChronic pulmonary disease (Heiner’s syndrome)AsthmaSkinUrticaria; angioedemaContact dermatitisAtopic dermatitisSystemicAnaphylaxis; food-associated,exercise-induced anaphylaxisddIgE, immunoglobulin ER. Berni Canani et al. / Nutrition 27 (2011) 983–987984