Pediatrics 2003 Sicherer 1609 16

2003;111;1609PediatricsScott H. Sicherer

Clinical Aspects of Gastrointestinal Food Allergy in Childhood

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Scott H. Sicherer, MD

ABSTRACT. Gastrointestinal food allergies are a spec-trum of disorders that result from adverse immune re-sponses to dietary antigens. The named disorders includeimmediate gastrointestinal hypersensitivity (anaphylax-is), oral allergy syndrome, allergic eosinophilic esophagi-tis, gastritis, and gastroenterocolitis; dietary protein en-terocolitis, proctitis, and enteropathy; and celiac disease.Additional disorders sometimes attributed to food al-lergy include colic, gastroesophageal reflux, and consti-pation. The pediatrician faces several challenges in deal-ing with these disorders because diagnosis requiresdifferentiating allergic disorders from many other causesof similar symptoms, and therapy requires identificationof causal foods, application of therapeutic diets and/ormedications, and monitoring for resolution of these dis-orders. This review catalogs the spectrum of gastrointes-tinal food allergies that affect children and provides aframework for a rational approach to diagnosis andmanagement. Pediatrics 2003;111:16091616; gastrointes-tinal allergy, food allergy, food hypersensitivity, oral tol-erance, mucosal immunology.

ABBREVIATIONS. IgE, immunoglobulin E; RAST, radioaller-gosorbent test; GER, gastroesophageal reflux; CMA, cow milkallergy.

The gastrointestinal tract is capable of display-ing a relatively narrow repertoire of symptomsand signs in response to disease: pain, nausea,vomiting, and diarrhea. If there is malabsorption orprotein loss, then additional manifestations of edemaand poor growth may ensue. The challenge for thepediatrician is to determine the cause of symptomsfrom a wide spectrum of disorders of diverse causesspanning infection, inflammation (Crohns disease,ulcerative colitis), anatomic problems (pyloric steno-sis), malignancy, and metabolic disorders of varioustypes. Among the causes to consider when evaluat-ing gastrointestinal complaints are those among thebroad category of adverse reactions to foods. Numer-ous food components can trigger symptoms; for ex-ample, bacterial toxins cause food poisoning, dietaryfats may elicit symptoms in those with disorders oflipid digestion (biliary disease), and lactose mayelicit symptoms in those with primary or secondary

deficiency of lactase. In contrast to the variety ofadverse food reactions caused by toxins, pharmaco-logic agents (eg, caffeine), and intolerance, food-al-lergic disorders are attributable to adverse immuneresponses to dietary proteins and account for numer-ous gastrointestinal disorders of childhood. This re-view catalogs the clinical manifestations, pathophys-iology, treatment, and natural course of a variety ofnamed gastrointestinal food hypersensitivity disor-ders that affect infants and children (Table 1)1,2 andalso discusses several other disorders sometimes at-tributable to food allergy. A general approach todiagnosis and management is provided.

DISORDERS THAT PRIMARILY AFFECT INFANTS

Dietary Protein-Induced Proctitis/ProctocolitisInfants with dietary protein-induced proctitis/

proctocolitis seem generally healthy but have visiblespecks or streaks of blood mixed with mucus in thestool.3,4 Blood loss is usually minimal, and anemia israre. The disorder manifests in the first severalmonths of life, with a mean age at diagnosis of 2months.5,6 The differential diagnosis includes causessuch as infection and anal fissures. The lack of sys-temic symptoms, vomiting, diarrhea, and growthfailure help to differentiate this disorder from othergastrointestinal food allergies that may also includecolitis. Cow milk proteins and, less commonly, soyprotein are the common triggers. Most infantspresent while being breastfed3,79 and are symptom-atic as a result of maternally ingested proteins ex-creted in breast milk. The disorder has also beennoted in infants who take casein hydrolysates.10 En-doscopic examination is often deferred but mayshow focal to diffuse colitis with edema and ero-sions. Biopsy reveals an eosinophilic infiltration andoccasionally lymphonodular hyperplasia.11,12

The mechanism underlying the disorder is un-known, but it is not associated with immunoglobulinE (IgE) antibody (prick skin tests/radioallergosor-bent tests [RASTs] are characteristically negative).Presumptive evidence to secure the diagnosis is ob-tained through a response to dietary elimination ofthe causal food protein. For breastfed infants, mater-nal restriction of cow milk (and more rarely otherfoods such as soy or egg) is required.3 If maternaldietary manipulations fail to resolve the bleedingand alternative diagnoses are excluded (by culture,biopsy, etc), then the physician may consider a trialof a hypoallergenic formula (eg, casein hydrolysate).However, there are currently no data to address theoutcome of continued breastfeeding despite mildbleeding in an otherwise healthy-seeming infant. For

From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergyand Immunology, Department of Pediatrics, Mount Sinai School of Medi-cine, New York, New York.Received for publication Sep 11, 2002; accepted Oct 30, 2002.Reprint requests to (S.H.S.) Division of Allergy/Immunology, Mount SinaiSchool of Medicine, Box 1198, One Gustave L. Levy Pl, New York, NY10029-6574. E-mail: [email protected] (ISSN 0031 4005). Copyright 2003 by the American Acad-emy of Pediatrics.

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cow milk- or soy formula-fed infants, substitutionwith a protein hydrolysate formula generally leadsto cessation of bleeding. An amino acid-based for-mula may be needed in those who have prolongedbleeding while taking an extensive hydrolysate.10,13Bleeding is expected to resolve within 72 hours ofdietary exclusion of the causal protein. Continuedbleeding may be an indication for referral for moreinvasive testing (ie, biopsy) and monitoring for ane-mia. The disorder should resolve by age 1 or 2 years,and the causal food protein can be gradually addedback to the diet at that time with monitoring forvisible blood. The disorder is not IgE antibody me-diated, so unless additional atopic disease developsin the patient, testing for IgE antibodies to the causalprotein is not needed.

Dietary Protein EnteropathyDietary protein enteropathy is characterized by

protracted diarrhea and vomiting (in two thirds)with resulting malabsorption and failure to thrivewith onset most commonly in infancy.1418 Protein-losing enteropathy may lead to edema, abdominaldistension, and sometimes anemia. The differentialdiagnosis must consider other causes of enteropathy(eg, infectious, metabolic, lymphangiectasia, Celiacdisease). The disorder is caused by an immune re-sponse most commonly to cow milk protein, but soy,cereal grains, egg, and seafood have also been impli-cated. Diagnosis is based on the combined findingsfrom endoscopy/biopsy, allergen elimination, andchallenge. Biopsy reveals variable small bowel villusinjury, increased crypt length, intraepithelial lym-phocytes, and few eosinophils. The immune mecha-nisms seem to involve T cell responses19 and are notassociated with IgE antibodies. Although featuresare shared with Celiac disease, this enteropathy isunlike Celiac disease because resolution generallyoccurs in 12 years and there is no increased threat offuture malignancy.16 Dietary protein enteropathymay persist into later childhood,20 but the frequencyof persistence of the disorder into adulthood is un-known.

Dietary Protein EnterocolitisThe symptoms observed in infants with dietary

protein enterocolitis seem similar to but more severethan those observed in protein enteropathy.2123 Be-cause both the small and large bowel are involved,the term enterocolitis is used. The disorder mustbe differentiated from nonallergic causes of entero-colitis (eg, infection, neonatal enterocolitis). Cowmilk protein is the most common cause, but approx-imately half of patients also react to soy. A variety ofadditional foods have been implicated, includingrice, oat and other cereal grains, and poultry.12,24,25During chronic or intermittent ingestion of the causalfood protein, infants may experience such severevomiting and diarrhea that dehydration, lethargy,acidosis, and methemoglobinemia may result,26 andinfants may seem septic with high peripheral bloodpolymorphonuclear leukocyte counts. Resolution ofsymptoms occurs after appropriate dietary exclu-sion. A distinct feature of this disorder is that rein-troduction of the causal protein leads to a delayed(2 hours) onset of dramatic symptoms that hasbeen used to confirm the diagnosis by oral foodchallenge.21,22,27 Confirmation of the allergy includesa negative search for other causes; improvementwhen not ingesting the causal protein; a positive oralchallenge resulting in vomiting/diarrhea; and evi-dence of gastrointestinal inflammation through stoolexamination for blood, eosinophils, and a rise in theperipheral polymorphonuclear leukocyte count over3500 cells/mL.22 Caution is needed when performingoral food challenges because approximately 20% ofreactions lead to shock.23 The diagnosis is usuallymade without biopsy, but colonic biopsies in symp-tomatic patients reveal crypt abscesses and a diffuseinflammatory cell infiltrate with prominent plasmacells; small bowel biopsies reveal edema, acute in-flammation, and mild villous injury.2731 The mech-anism underlying this disorder seems to involve amilk-specific T cell response with elaboration of thecytokine tumor necrosis factor- that may also ac-count for some of the systemic symptoms.3234 That

TABLE 1. Named Gastrointestinal Food-Allergic Disorders of Infancy and Childhood

Disorder Key Symptoms/Signs/Features

IgE antibody mediated, acute onsetImmediate gastrointestinal hypersensitivity Acute onset nausea, emesis, pain; diarrhea may follow; foods: milk, egg,

wheat, soy, peanut, tree nuts, seafoodOral allergy syndrome Pruritus, mild edema confined to oral cavity caused by IgE antibodies

originally induced by pollen sensitization that react with homologousproteins in certain uncooked fruits/vegetables

IgE antibody associated in some cases/cell mediated,delayed-onset/chronic

Eosinophilic gastroenteropathies Symptoms vary upon site(s)/degree of eosinophilic inflammation;esophageal: dysphagia, pain; generalized: ascites, weight loss, proteinlosing enteropathy, edema, obstruction; multiple foods

Cell-mediated, delayed-onset/chronicDietary protein enterocolitis Chronic exposure: emesis, diarrhea, poor growth, lethargy; reexposure

after restriction: emesis, diarrhea, hypotension (15%) 2 h afteringestion; foods: milk, soy, grains

Dietary protein proctitis Mucousy, bloody stools; causes: breast milk with maternal cow milkingestion, cow milk

Dietary protein enteropathy Malabsorption, edema, emesis, poor growth, usually caused by cow milkCeliac disease Malabsorption, diarrhea, response to gluten, HLA-DQ2 associated

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several foods are often involved may reflect a moreglobal problem in immune tolerance for these in-fants. The disorder is not associated with IgE anti-body (but a small subset of patients may eventuallyestablish IgE antibody responses).23 Considering thehigh rate of co-allergy to cow milk and soy, treat-ment with a hypoallergenic formula (casein hydro-lysate) is suggested and usually effective (if not, thenan amino acid-based formula can be used). It may beadvisable to delay the introduction of other aller-genic foods, especially grains, in these children.Treatment of acute reactions (reexposure) may re-quire fluid resuscitation, and administration of ste-roids has been suggested.23 Most infants outgrow theallergy by age 2 or 3 years, but some seem to main-tain hypersensitivity into childhood.35 Because reso-lution must be proved through oral challenges thatcan induce severe reactions, evaluation must be un-dertaken cautiously under supervision in a con-trolled setting, usually with intravenous access inplace.

Additional Disorders Related Primarily to Cow MilkHypersensitivity

Gastroesophageal RefluxOn the basis of studies using cow milk elimination

and challenge, it is clear that a subset of infantilegastroesophageal reflux (GER) is attributable to cowmilk allergy (CMA).3641 The magnitude of the prob-lem is not well-defined; it has been estimated that in16% to 42% of infants, GER is attributable toCMA.37,39,40 Risk factors for milks being causal seemto include esophagitis, malabsorption, diarrhea, andatopic dermatitis. Thus, for many infants with cowmilk-associated GER, the reflux is not an isolatedsymptom. One group3840 identified that in infantswith CMA-induced GER, the pH probe shows aphasic pattern with a gradual and prolonged fall inpH after milk ingestion. This is in contrast to the pHprobe pattern seen with typical GER in which thereare multiple, random, sharp decreases in pH. How-ever, the phasic pattern has not been demonstratedby other investigators.42 Taking the studies together,it is evident that CMA accounts for GER in someinfants, but other causes must also be considered (eg,obstruction, metabolic disorders, and other inflam-matory disorders). Particularly when there are addi-tional symptoms of CMA and/or poor responses toother measures (medications), a trial elimination dietmay be warranted.

Infantile ColicThere is some evidence that infantile colic is asso-

ciated with CMA, but the strength of the relationshipis not well-defined. Infants who are experiencingsymptoms of CMA have a high rate (44%) of colic,and hypoallergenic formulas are more efficacious forcolic than antacids or low-lactose formula.43,44 How-ever, the role of allergy as opposed to other causesamong those with colic and without other symptomsof food allergy remains controversial and in need ofadditional study. For example, there does not seemto be an increased rate of atopy in infants with col-

ic.45 In regard to trials of therapy, a meta-analysis of27 trials identified through Medline and the Co-chrane Controlled Trials Register concluded that in-fantile colic should preferably be treated by reducedstimulation (effect size 0.48) and a 1-week trial ofsubstitution of cow milk formula with hypoaller-genic formula (effect size 0.22 based on 2 studies).44The formula suggested by these authors for substi-tution was an hydrolysate because the data are lessconvincing or incomplete for soy and low-lactoseformula. They suggested a trial of milk exclusion inthe diet of lactating mothers.

DISORDERS THAT AFFECT BOTH INFANTS ANDCHILDREN

Immediate Gastrointestinal HypersensitivitySymptoms of immediate gastrointestinal hyper-

sensitivity are acuteusually within minutes or upto 1 to 2 hoursand include nausea, vomiting, andabdominal pain usually within minutes of ingestion.Diarrhea may follow several hours after the initialsymptoms. Unlike the disorders described above,this disorder is mediated by IgE antibody directed tofood proteins. These IgE antibodies provide a mech-anism for food-specific mediator release (eg, hista-mine) from mast cells. Although immediate, IgE-mediated gastrointestinal reactions may occurwithout other systemic symptoms; they are morecommonly associated with reactions in other organsystems, such as during systemic anaphylaxis in pa-tients with other atopic diseases. For example, chil-dren with atopic dermatitis undergoing oral foodchallenges with foods to which they have specific IgEantibody will sometimes manifest only gastrointesti-nal symptoms.46,47 In addition to a suggestive his-tory, allergy prick skin tests and RASTs to the causalprotein will be positive. The usual offenders aremilk, egg, peanut, soy, wheat, and seafood. Similar toother IgE-dependent allergic disorders, allergy tomilk, egg, wheat, and soy generally resolves,whereas allergies to peanuts, tree nuts, and seafoodare more likely to persist.

Eosinophilic Gastroenteropathies (EosinophilicEsophagitis, Gastroenterocolitis, and Gastritis)

This heterogeneous group of eosinophilic gastro-enteropathies has in common an eosinophilic inflam-mation of the gut. The nomenclature used to describeparticular disorders relates to the locations of eosin-ophilia; the depth and severity of eosinophilic in-flammation influences the symptoms. Named sub-types include allergic eosinophilic gastritis, allergiceosinophilic gastroenterocolitis, and allergic eosino-philic esophagitis. The symptoms caused by thesedisorders overlap those caused by many other patho-logic gastrointestinal processes: postprandial nausea,dysphagia, abdominal pain, vomiting, and diarrhea,and if inflammation is very dense, obstruction canresult. Small bowel involvement may result in pro-tein-losing enteropathy and weight loss. Serosal in-volvement can induce eosinophilic ascites. The dis-order requires confirmation of an eosinophilicinfiltration of the gut by biopsy (sometimes patchy)

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and elimination of other causes of eosinophilia, suchas parasites, inflammatory bowel disease, and vas-culitis. All age groups may be affected, and the dis-order has been diagnosed in preterm infants withsymptoms that overlap those of necrotizing entero-colitis.48 Peripheral eosinophilia is sometimes ob-served (50% of patients).49,50 The pathophysiologicbasis of the disorder has remained elusive, and therole of allergens is debated. At least a subset of thosewith the disorder are food responsive and reactive tothe usual causative agents (eg, milk, egg, wheat, soy)but with an increased degree of multiple food aller-gies. In patients with food-responsive eosinophilicgastroenteropathies, the pathophysiological mecha-nisms seem to include both cell-mediated and IgEantibody-mediated forms.

Perhaps the most common type of eosinophilicgastroenteropathy and most difficult to diagnose andmanage is allergic eosinophilic esophagitis. This dis-order is particularly challenging to diagnose becausethe symptoms overlap those of GER. Patients withallergic eosinophilic esophagitis have a predomi-nance of dysphagia (85%), and there is an overrep-resentation of young, atopic male patients.5155 Al-though symptoms overlap those of GER, in somepatients reflux is absent on pH probe. Some authorshave evaluated the number of eosinophils per high-power field as a means to differentiate this disorderfrom GER, and when the numbers exceed 7, espe-cially when they are 24, allergic and/or intrinsiceosinophilic inflammation is likely.52,5661 In this sce-nario, medical treatment for GER may fail, but anti-inflammatory medications such as oral steroids haveproved efficacious.61 The ability of dietary manage-ment to ameliorate the inflammation has beenproved62 but is not universally curative.52 Orensteinet al52 documented positive prick skin tests or RASTsin 13 of 19 children with eosinophilic esophagitis(median: 7 foods). Dietary elimination was under-taken in 12 of the 13 with positive tests. Of 10 whowere compliant with the diet, all were believed tobenefit with resolution of symptoms. Seven of thepatients had concomitant therapies (steroid, 3; anti-reflux medications, 2; cromolyn, 1; or fundoplication,1); however, lapses in the diet were accompanied byrecurrence of symptoms in the months after diagno-sis despite the other therapies. In a study that spe-cifically addressed the role of food allergy in childrenwith eosinophilic esophagitis, Kelly et al62 evaluatedpatients for whom standard GER treatment or fun-doplication failed (6 patients) and who had persis-tent eosinophilia on esophageal biopsy. These pa-tients were placed on a very restricted diet (12 solidfoods, eg, apple, corn) and an amino acid-based for-mula. Eight of 10 patients became symptom-free, and2 had significant reduction in symptoms within 2 to6 weeks after starting the dietary program. The pa-tients also demonstrated a decline in the mediannumbers of eosinophils from 40 to 0.5/high-powerfield. The causal foods were primarily milk, soy, egg,peanut, and wheat. The correlation of causal foodswith positive skin test results was poor, and im-proved diagnostic methods are under investiga-tion.63 Oral steroids have been effective, including

case reports of high-dose inhaled/swallowed ste-roids (eg, the off-label use of inhaled steroidssprayed into the mouth and swallowed),64 and ad-ditional anti-inflammatory therapies such as cro-molyn52 and leukotriene antagonists have been triedbut require additional study.65,66 A trial of an ele-mental diet may prove beneficial in many of thesepatients,67 but the process of identifying causal aller-gens is time-consuming and often frustrating. If thereis a response to elimination dietswhich entails atleast 6 weeks on the diet and may require a biopsy toconfirmthen foods are slowly added back into thediet. The onset of symptoms after addition of a prob-lematic food may be delayed, adding to the diagnos-tic difficulties.

The natural course of the allergic eosinophilic gas-troenteropathies is not well-defined. For at leastsome patients, the disorder seems to be long-livedand can continue (or present) through adulthoodwith a waxing and waning course with an element ofimprovement over time.49

DISORDERS THAT GENERALLY PRESENTOUTSIDE INFANCY

Oral Allergy Syndrome (Pollen-Food Syndrome)Individuals with oral allergy syndrome, an IgE

antibody-mediated disorder, experience prompt oralpruritus and sometimes angioedema of the lips,tongue, and palate when ingesting certain freshfruits and vegetables.68 The expression of this aller-gic response requires initial sensitization via the re-spiratory route to pollens that contain proteins thatare homologous to those found in particular fruitsand vegetables. Individuals with this syndrome,therefore, usually have a history of seasonal allergicrhinitis (hayfever). Examples of the associated pol-lens and foods include reactions to melons in indi-viduals with ragweed allergy and reactions to ap-ples, peaches, and cherries in those with birch pollenallergy. The proteins are labile, and cooked forms ofthe fruits and vegetables generally do not inducesymptoms. Similarly, it is assumed that systemic re-actions are averted because the proteins are easilydigested. However, 9% of individuals experiencesymptoms beyond the mouth, and 1% to 2% experi-ence severe reactions.69 Allergy skin tests using freshextracts of the implicated food are characteristicallypositive.

Celiac DiseaseCeliac disease represents an immune response to a

food protein (gluten) and therefore may be consid-ered a food-allergic disorder.70,71 Symptoms includevomiting, diarrhea, anorexia, and growth failure. Ini-tial symptoms may present in the first year of life,but characteristic clinical features usually manifestafter age 1 year. The disorder is caused by gliadin-specific T cell responses enhanced by deamidatedgliadin produced by tissue transglutaminase. Anti-gen presentation is central as 95% of patients areHLA DQ2. The symptoms include protein-losing en-teropathy and growth failure. A full discussion ofdiagnosis and management is beyond the scope ofthis review.


Chronic ConstipationCow milk intolerance has been suggested as a

cause of chronic constipation in older infants andtoddlers.7275 Considering potential selection biasand paucity of studies, it is difficult to know whatpercentage of constipated children may be cow milkresponsive. Among small groups of selected patients,responsiveness was 28% to 68%.74,75 There may be animmunologic basis because investigators have dem-onstrated a higher rate of atopic disease, rectal mu-cosal inflammation, and IgE antibodies in the milk-responsive group.74 In these studies, substitutionwith soy or other foods may have also had a nonim-munologic laxative effect. No specific recommenda-tions have been made, but prudence may suggestthat a trial of dietary elimination of cow milk beundertaken for recalcitrant constipation unrespon-sive to other therapies. Additional studies areneeded to confirm the specific associations.

APPROACH TO DIAGNOSIS AND MANAGEMENTAdditional reviews in this series address the gen-

eral scheme for the diagnosis and management offood allergy in infants and children. What is empha-sized here are the features that may indicate to thepediatrician that food hypersensitivity may be acause of observed gastrointestinal disease. The pedi-atrician who is evaluating an infant or child withsymptoms/signs of gastrointestinal disease must de-termine the cause from among a wide variety ofpossibilities, including infection, metabolic disorder,anatomic disorders, etc. Adverse responses to inges-tants remains 1 of the possibilities, and within thisbroad category one must consider both immunologic(allergic) and nonimmunologic (intolerance, pharma-cologic effects, food poisoning, etc) causes.

A recent consensus workshop (Workshop on theClassification of Gastrointestinal Diseases of Infantsand Children, November 1998, Washington, DC)1considered a variety of factors in establishing a di-agnosis of food allergy in gastrointestinal disorders.These elements are summarized in Table 2 and takeinto consideration the variety of clinical manifesta-tions of food-allergic disorders and the overlap withnonfood-allergic disorders. Consequently, 1 singlerecommendation cannot be made for diagnosing gas-trointestinal food allergy, and proof of underlyingimmunologic mechanisms is lacking for most of thedescribed disorders, except for those mediated byfood-specific IgE antibodies. It should also be ac-knowledged that symptoms often overlap (eg, vom-iting and diarrhea) and patients may not always fitneatly into 1 category (eg, proctitis as differentiatedfrom a very mild manifestation of enterocolitis).

Co-consideration of the features indicating a highlikelihood of allergic gastrointestinal disease (Table2), along with an appreciation for the named food-allergic disorders that affect the gut (Table 1), pro-vides an essential staring point for the evaluation ofthe role of food allergy in gastrointestinal disease.For immediate reactions that are likely to be IgEantibody-mediated, ancillary tests such as prick skintests or RASTs are helpful in verifying suspicions

obtained in the history. In some cases, oral foodchallenges may be needed for additional verification.However, the majority of gastrointestinal food hy-persensitivity disorders are not mediated by IgE an-tibody, and so the evaluation is much more depen-dent on the results of elimination diets, selected oralfood challenges, and biopsies as indicated. Unlikethe evaluation for food allergy in skin or respiratorydisease, for gastrointestinal food allergy a number ofancillary tests, often administered by gastroenterol-ogists and allergists, may be needed to determine thediagnosis (Table 3). Additional tests that may havevalue, such as patch testing with foods,63 are understudy. Patch testing with foods involves the place-ment of a food extract under occlusion on the skin for24 hours with observation at 24 and 48 hours afterremoval for erythema and papules indicated a de-layed-type hypersensitivity response. More study isneeded before such tests can be generally recom-mended. Table 4 summarizes features that are help-ful for the evaluation of specific clinical disorders.Table 5 summarizes clinical circumstances that sug-gest consideration for food allergy as a cause.

A number of tests are of unproven utility andshould not be used. These include measurement ofIgG4 antibody, provocation-neutralization (dropsplaced under the tongue or injected to diagnose and

TABLE 2. Elements Suggesting Food Allergy as a Cause ofGastrointestinal Disease

1) Temporal relationship of characteristic symptoms toparticular foods

2) Exclusion of anatomical, metabolic, infectious and otherinflammatory causes

3) Pathologic findings consistent with an allergic cause (e.g.,eosinophilia)

4) Confirmation of a relationship between ingestion of thespecific dietary protein and symptoms by clinical challengesor repeated exposures

5) Evidence of the food specific IgE antibody in settings ofIgE-mediated disease

6) Associated atopic disease (atopic dermatitis, asthma)7) Failure to respond to conventional therapies aimed at

anatomical, functional, metabolic or infectious causes8) Improvement in symptoms with elimination of the causal

dietary protein(s)9) Clinical response to treatments of allergic inflammation (i.e.-

corticosteroids)10) Similarities to clinical syndromes either proven or presumed

to be caused by immunologic mechanisms11) Lack of other explanations for the clinical allergic-like

reaction

Adapted from Sampson and Anderson.1

TABLE 3. Laboratory Tests Used in the Evaluation of FoodAllergy in Gastrointestinal Disorders*

Primary tests for specific IgE antibody to particular foods, asindicated

RAST (radioallergosorbent test)Prick/puncture skin tests

Adjunctive testsEndoscopy/biopsyAbsorption studiesStool analysis (heme, leukocytes, eosinophils)pH probe

* Tests are selected on the basis of individual disorders/symptomcomplexes.


treat various symptoms), and applied kinesiology(muscle strength testing).76

Therapy in infants often requires selection of analternative formula. In infants with IgE-mediatedCMA, most (86%) will tolerate a soy formula,77 butthe rate of tolerance is lower (50%) for most of thecell-mediated disorders.23 Infants with true CMAwould be expected also to react to partially hydro-lyzed formula, lactose-free cow milk-based formula,and most mammalian milks (eg, sheep, goat),78 sonone of these is a good alternative. In most cases(95%), infants with CMA will tolerate extensivelyhydrolyzed cow milk formula, but for the few whocontinue to react (presumably as a result of residualallergens), an amino acid-based formula is requiredfor therapy.10,67,7981

Although therapy of gastrointestinal food hyper-sensitivity disorders includes dietary restriction, thegood news is that most of the disorders resolve withtime. Hence, a central aspect of management is peri-odic reevaluation (oral food challenge) for determi-nation of tolerance, a procedure that often requiresthe specific expertise of an allergist or gastroenterol-ogist if acute or severe reactions are possible. Hope-fully, the coming years will bring improved diagnos-tic, therapeutic, and preventive strategies for bettermanagement of these conditions.

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TABLE 4. Features and Diagnostic Tests Helpful for Diagnosis

Disorder Under Consideration CentralDiagnostic Tests*

Additional DiagnosticTests

Natural Course Routine for Follow-up

Immediate gastrointestinalhypersensitivity

PST, RAST OFC Depends upon food Repeat PST/RAST, OFC

Oral allergy syndrome PST OFC, RAST Prolonged PST, RAST, OFC ifsuspected resolution

Eosinophilic gastroenteropathies Biopsy, ED PST, RAST, OFC Prolonged Biopsy, OFC, PST, RASTDietary protein enterocolitis ED (OFC) PST, RAST, OFC,

sepsis evaluation2 y OFC

Dietary protein proctitis ED Usually none, biopsyif recalcitrant, stoolculture

12 y Gradual reintroduction

Dietary protein enteropathy Biopsy, ED PST, RAST, OFC 2 y OFCMilk-induced reflux, colic, or

constipationED and OFC pH probe, biopsy,

trial refluxmedications

Reflux/colic-resolvesbeyond age 12 y

OFC

Celiac disease Serologies, biopsy Permanent Routine health visits

PST indicates prick skin test; ED, elimination diets; OFC, oral food challenge.* The history is paramount to the diagnosis of all of the disorders. May be needed to verify specific foods involved, selected on the basis of various needs (nutrition, ruling out other disorders, etc).

TABLE 5. Summary: Specific Clinical Scenarios That MayWarrant Evaluation for Food Allergy or Intolerance

Immediate gastrointestinal responses (oral pruritus, vomiting,diarrhea) after ingestion of particular food(s)

Mucousy/bloody stools in an infantMalabsorption/protein-losing enteropathySubacute/chronic vomiting, diarrhea, or dysphagiaFailure to thriveGastrointestinal symptoms in a patient with atopy (eg, atopic

dermatitis)Gastroesophageal reflux disease recalcitrant to typical therapiesInfantile colic poorly responsive to behavioral interventionsChronic constipation recalcitrant to typical management


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