AGA technical review on the evaluation of food allergy in gastrointestinal disorders
This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice and Pratice Economics Committee. The paper was approved by the committee on September 23, 2000, and by the AGA Governing Board on November 12, 2000.
Abbreviations: CMA , cow’s milk allergy, EE , eosinophilic esophagitis, EG , eosinophilic gastroenteritis, FPIES , food protein–induced enterocolitis syndrome, GER , gastroesophageal reflux, IE , intraepithelial eosinophil, PMN , polymorphonuclear, RAST , radioallergosorbent test
The term food allergy refers to an adverse immunologic response to proteins in food1, 2; it is thus to be distinguished from other, more common, adverse reactions to foods that are designated food intolerance. Adverse reactions caused by food intolerance may result from particular constituents within foods, such as toxins (e.g., food poisoning) or pharmacologic agents (e.g., caffeine or tyramine), or from host factors such as metabolic disorders (i.e., lactase deficiency). The aim of this technical review is to provide a rational approach to the evaluation of food allergy in gastrointestinal disorders by (1) providing a conceptual framework through a brief review of the clinical manifestations of food allergy and their presumed pathophysiology, (2) reviewing particular gastrointestinal disorders/symptom complexes that may be associated with food allergy, and (3) reviewing diagnostic approaches to food allergy.
Because food allergy is not a single disorder, but rather immunopathologic mechanisms underlying a number of defined or poorly defined gastrointestinal disorders/symptom complexes, a variety of strategies were undertaken in selecting articles for this review. MEDLINE searches were conducted for peer-reviewed clinical studies of particular disorders using MeSH (National Library of Medicine Medical Subject Headings) terms for the disorder plus the term “food hypersensitivity.” In addition, more general searches were conducted for food hypersensitivity disorders. However, the lack of standard approaches to evaluate food allergy, overlap of clinical manifestations of various disorders, the preponderance of case reports or small, uncontrolled studies, and deficiencies in study design frequently limited the conclusions that could be drawn and precluded meta-analyses. To develop recommendations for evaluating the possibility of food allergy in patients with various clinical syndromes/symptoms, this report highlights results from larger, controlled studies; approaches from placebo-controlled, blinded studies; and consensus panel reports.
There are no population-based studies that specifically address the epidemiology of food allergy. However, in a population-based study of food intolerance among 15,000 households in the United Kingdom, considering 8 foods and conducting blinded challenges in a subgroup of adults, Young et al.3 identified a reaction rate of 1.4%. This contrasts sharply to the high rate of perceived food allergy among adults (~20%).3 Documented adverse reactions to food seem to be more common in infants/children. Bock4 studied an unselected clinic population of 480 infants followed up prospectively to age 3 years and evaluated with blinded oral food challenges. Six percent had confirmed food reactions (excluding reactions to fruit juice), but most outgrew their sensitivity by age 3. Cow’s milk was responsible for most of the reactions in these infants. Indeed, reaction to cow’s milk protein in infants seems to be distinctly common and has been evaluated in 3 separate prospective studies that used oral food challenges, each including more than 1000 unselected newborns followed up prospectively in Sweden,5 Denmark,6 and The Netherlands.7 These studies documented a prevalence of milk allergy of 1.9%, 2.2%, and 2.8%, respectively. The percentage of the infants with gastrointestinal reactions was 60%, 59%, and 50%, respectively.
In studies using double-blind, placebo-controlled food challenges to determine food allergy in children with atopic dermatitis, it has been noted that a short list of foods accounts for the majority of reactions. In a representative study by Burks et al.8 of 165 children with a mean age of 4 years, 7 foods accounted for 89% of the positive challenges: milk, egg, peanut, soy, wheat, fish, and tree nuts. During these challenges, 27% responded with gastrointestinal symptoms, and 7% of the total group experienced isolated gastrointestinal symptoms. However, virtually any food protein can elicit an immunologic response, and foods such as fish, rice, and chicken have also been reported to cause isolated gastrointestinal allergic responses.9 Taken together, these studies substantiate the notion that food allergy is more common among infants and young children compared with adults and that a small number of foods are responsible for a majority of the reactions, with cow’s milk being a major offender among infants.
Clinical manifestations and pathophysiology
Although the gastrointestinal tract has stereotypical responses to insults that include a fixed set of clinical symptoms, food allergic reactions affecting the gut can be conceptually divided between 2 major spectra: (1) isolated gut reactions vs. reactions associated with responses in other organ systems (respiratory, skin, or cardiovascular) and (2) acute/subacute onset vs. chronic/persistent symptoms. These distinctions are important both in considering which patients are likely to have food allergy and the manner of diagnostic approach (laboratory testing or oral food challenge). These clinical spectra may also reflect, with some overlap, the immune mechanisms responsible for the food allergic responses.
The most clearly delineated food-allergic reactions are mediated by immunoglobulin (Ig) E antibodies specific to particular food proteins. These food-specific IgE antibodies bind high-affinity receptors on the surfaces of mast cells and basophils. When the food protein penetrates mucosal barriers, binds, and cross-links these antibodies, the cells are activated and release mediators (histamine, prostaglandins, and leukotrienes) that initiate vasodilatation, mucous secretion, smooth muscle contraction, and influx of other inflammatory cells. The variety of symptoms induced by IgE-mediated reactions includes not only the gastrointestinal tract, with vomiting, abdominal pain, diarrhea, and oropharyngeal pruritus, but also skin symptoms such as urticaria, angioedema, upper and lower airway symptoms (rhinitis or wheezing), and, potentially, cardiovascular symptoms, including anaphylactic shock. Thus, the IgE-mediated gastrointestinal reactions generally are acute in onset (minutes to several hours) and rarely isolated to the gastrointestinal tract.
Non–IgE-mediated gastrointestinal reactions are presumed to occur because of the elaboration of various cytokines secreted by antigen-presenting cells or T cells after recognition of particular food proteins. Heyman et al.10 evaluated 10 infants with gastrointestinal cow’s milk allergy (CMA) diagnosed by oral challenge and nonallergic controls for the response of peripheral blood lymphocytes to in vitro stimulation with cow’s milk protein. They found that the cells from infants with active allergy elaborated a significantly higher concentration of tumor necrosis factor α, and that this cytokine could induce alteration in epithelial cell barrier function. Subacute/chronic symptoms caused by food allergy seem to be non–IgE mediated, but more research is needed to determine the exact immunopathophysiology of these disorders.
However, there are food allergic disorders that present with chronic symptoms caused by IgE-mediated reactivity. For example, children with atopic dermatitis and evidence of food-specific IgE who develop acute gastrointestinal symptoms during oral food challenges may, while ingesting a food over a prolonged period, develop chronic complaints, including intermittent pain, vomiting, and diarrhea. Lactulose absorption is increased in these patients and reverts to normal when the causal food allergen is removed from the diet.11
Specific disorders and symptom complexes
In addition to considering whether gastrointestinal reactions caused by food allergy are isolated or associated with other allergic disease and are acute or chronic, it is helpful to consider particular symptom complexes/clinical syndromes in which food allergy is a possible cause. The following section specifically addresses the role of food allergy in these disorders.
Immediate (IgE-mediated) gastrointestinal reactions to food protein
Immediate gastrointestinal hypersensitivity
In immediate gastrointestinal hypersensitivity, ingestion of the causal protein results in immediate (from minutes to 1–2 hours) gastrointestinal symptoms that may include nausea, vomiting, abdominal pain, and diarrhea. Considered here as a distinct syndrome, it is more commonly associated with reactions in other organ systems, such as during systemic anaphylaxis in patients with other atopic diseases. For example, children with atopic dermatitis undergoing oral food challenges with foods to which they have specific IgE antibody will sometimes manifest only gastrointestinal symptoms.8, 12 In addition to a suggestive history, tests for specific IgE antibody to the causal protein will be positive.
Oral allergy syndrome
Oral allergy syndrome is a form of contact allergy confined almost exclusively to the oropharynx. Symptoms include pruritus and angioedema of the lips, tongue, and palate and are of rapid onset, typically while eating certain fresh fruits and vegetables.13 The reaction generally occurs in adults with pollen allergy (hayfever) sensitized to cross-reacting proteins in particular fruits and vegetables. Examples include reactions to melons in individuals with ragweed allergy and to apples in those with birch pollen allergy. The proteins are labile, and cooked forms of the fruits and vegetables generally do not induce symptoms. Allergy skin tests using fresh extracts of the implicated food are characteristically positive.
Dietary protein–Induced proctitis/proctocolitis of infancy
Food allergy is the major cause of rectal bleeding due to colitis in infants.14 Infants with this disorder are typically healthy but have specks or streaks of blood mixed with mucus in otherwise normal-appearing stool. Occasionally there is associated fussiness or increased frequency of bowel movements. The presence of vomiting, chronic diarrhea, significant anemia, or growth failure should raise suspicion of enteropathy or enterocolitis syndrome, a potentially more serious condition discussed below. The mean age at diagnosis is approximately 60 days, but there is often a history of bleeding that precedes diagnosis by several weeks15 and may be mistakenly attributed to perirectal fissures. Bleeding rarely occurs in the first week of life.16 On endoscopic examination, patchy erythema and loss of vascularity may be limited to the rectum, or it may extend throughout the colon.14 Lymphonodular hyperplasia may be seen but is not unique to this condition.15, 17 Histologically, high numbers of eosinophils or eosinophilic “abscesses” in the lamina propria (>60),17 crypt epithelium, and muscularis mucosa are typically observed.18 Multinucleated giant cells in the submucosa have been reported.19 Cryptitis and crypt abscesses containing polymorphonuclear (PMN) cells are uncommon in this condition, as are chronic changes such as glandular distortion and Paneth cell metaplasia. The immunologic mechanisms responsible are unknown. Although peripheral eosinophilia and positive radioallergosorbent tests (RASTs) to milk have been reported, the findings are not consistent.14, 18, 20, 21 The dietary proteins frequently implicated include cow’s milk and soy. The condition also occurs in exclusively breast-fed infants20, 21, 22 and in infants fed protein hydrolysate formulas23 that contain minute amounts of allergenic protein.
In cow’s milk or soy formula–fed infants, substitution with a protein hydrolysate formula generally leads to cessation of obvious bleeding within 72 hours, although it is unknown how long occult bleeding continues. The majority of infants who develop this condition while ingesting protein hydrolysate formulas will experience resolution of bleeding with the substitution of an amino acid–based formula.23, 24 Management in breast-fed infants is more difficult. Restriction of cow’s milk, egg, or soy from the mother’s diet usually results in prompt resolution of symptoms.22 In cases in which there is no response to maternal dietary manipulation, there are no data currently available to know whether breast-feeding may be safely continued in an infant who otherwise appears healthy.
Thus, the diagnosis of dietary protein proctocolitis is primarily clinical. Withdrawal of the presumed allergen and resolution of symptoms are usually sufficient to make the diagnosis, and the majority of infants will tolerate cow’s milk and soy products by 1–2 years of age. Continued bleeding may be an indication for more invasive testing (i.e., biopsy) and monitoring for anemia.
Dietary (food) protein–Induced enteropathy
This is a symptom complex of malabsorption, failure to thrive, diarrhea, emesis, and hypoproteinemia in infants that is usually related to an immunologic reaction to cow’s milk protein.25, 26, 27, 28, 29 The syndrome may also occur following infectious gastroenteritis in infants.27, 30 Patchy villous atrophy with cellular infiltrate on biopsy is characteristic. Diagnosis is based on the combined findings from endoscopy/biopsy, allergen elimination, and challenge. There are case reports in which similar symptoms occur with foods other than milk (eggs, rice, poultry, fish, or shellfish), occasionally affecting older individuals, but larger series are lacking. Although it shares features with celiac disease, this disorder generally resolves in 1–2 years.27
Dietary (food) protein–Induced enterocolitis syndrome
Food protein–induced enterocolitis syndrome (FPIES), as defined by Powell,31, 32 describes a symptom complex of profuse vomiting and diarrhea diagnosed in infancy. Because both the small and large bowel are involved, the term “enterocolitis” is used. Although the clinical syndrome may represent a more severe form of food protein–induced enteropathy (abdominal symptoms and malabsorption with associated villous blunting27), there are particular features, including signs of systemic reactivity and implications for long-term clinical management, that warrant its discussion as a distinct clinical entity.
Powell31 described 9 infants with severe, protracted diarrhea and vomiting. The symptoms developed 4–27 days after birth (mean, 11 days) while the infants were receiving cow’s milk–based formula. Switching to a soybean–based formula resulted in transient improvement, but symptoms generally recurred in 7 days. Seven of the 9 infants were below birth weight, and 8 of 9 presented with dehydration. Eight of the infants appeared acutely ill and underwent sepsis evaluations (negative). All infants were noted to have low serum albumin levels, increased peripheral blood PMN leukocyte counts, and stools that were positive for heme and reducing substances. The hospital course usually involved improvement while on intravenous fluids, followed by recurrence of dramatic symptoms with reintroduction of soy- or cow’s milk–based formula, including the development of shock in several infants. Follow-up with oral challenges was carried out with cow’s milk and soybean formulas (30–100 mL of formula) at a mean age of 5.5 months, and 14 of 18 challenges were positive. Ten of 14 challenges resulted in vomiting (onset, 1–2.5 hours after ingestion; mean, 2.1 hours), and all experienced diarrhea (onset, 2–10 hours; mean, 5 hours) with blood, PMN cells, eosinophils, and increased carbohydrate in the stool. There was an increase in PMN cell counts in all positive challenges, peaking at 6 hours after ingestion, with a mean increase of 9900 cells/mm3 (range, 5500–16,800 cells/mm3). Only isolated gastrointestinal symptoms were reported.
The results of these studies31, 33 led Powell to propose particular criteria for a positive oral challenge to diagnose food protein–induced enterocolitis of infancy.32 Confirmation of the allergy included a negative search for other causes, improvement when not ingesting the causal protein, and a positive oral challenge resulting in vomiting or diarrhea, evidence of gastrointestinal inflammation through stool examination for heme, eosinophils, and an increase in the peripheral PMN leukocyte count of >3500 cells/mL. Infants with symptoms consistent with severe enterocolitis who fulfilled, or who are highly likely to have fulfilled, these criteria are included in many reports of milk or soy allergy of infancy.10, 25, 34, 35, 36, 37, 38, 39 Additional information about the clinical characteristics of these infants has emerged. In a review of 17 infants hospitalized with FPIES, Murray and Christie40 reported 6 infants who presented with acidemia (mean pH, 7.03) and methemoglobinemia. The association of methemoglobinemia with FPIES was noted in the investigators’ published experience with FPIES.41 Several other clinical features of infantile FPIES have emerged from studies by Sicherer et al.41 (16 patients) and Burks et al.39 (43 patients). All of the infants studied had negative skin prick tests or RASTs to the causal proteins (cow’s milk or soy). Approximately half of the infants reacted to both cow’s milk and soy. After 2 years from the time of presentation, sensitivity to milk was lost in 60%, and to soy in 25% of the patients. Treatment with a hydrolyzed cow’s milk formula is advised, although some patients may react to the residual peptides in these formulas, thus requiring an amino acid-based formula.42 Most of these infants become tolerant of the causal protein 1–2 years after the diagnosis, but a subset may have more prolonged sensitivity.41
Because infantile FPIES is a diagnosis that can be made clinically, there are no series in which biopsies are performed solely in patients fulfilling Powell’s criteria. Thus, specific descriptions of the histologic findings are lacking, and only assumptions can be drawn by considering descriptions from case reports or series that likely included these patients. Endoscopic and biopsy findings in FPIES are nonspecific. Colonic biopsies performed in symptomatic patients reveal crypt abscesses and a diffuse inflammatory cell infiltrate with prominent plasma cells; small bowel biopsies reveal edema, acute inflammation, and mild villous injury.43, 44, 45, 46, 47 In some cases, focal erosive gastritis and esophagitis are found with prominent eosinophilia and villous atrophy.45, 48, 49
In an unpublished study, the investigators observed adults who experience a delayed onset of severe, repetitive vomiting and delayed diarrhea after ingestion of shellfish. The response is not associated with specific IgE antibody and occurs stereotypically with repeated exposure. This may represent a variation of enterocolitis syndrome that occurs in adults.
Gastroesophageal reflux associated with CMA in infants
CMA and gastroesophageal reflux (GER) are both common conditions in the first year of life that have similar symptoms, such as vomiting and irritability.50, 51 In 1985, Forget et al.48 showed that infants who seem to have GER but who do not respond to medical therapy might have CMA. A number of recent studies have attempted to show that CMA may induce symptoms of GER and may be associated with distinctive serologic and pH probe characteristics.
Staiano et al.52 identified a cohort of infants with vomiting and showed that 16% of patients had both GER and CMA, whereas 16% had CMA alone. GER was defined on the basis of a positive pH probe and esophagitis on biopsy. CMA was defined on the basis of resolution of symptoms after removal of cow’s milk protein and a recurrence upon oral challenge 4–6 weeks later. Small intestinal biopsies and intestinal permeability studies were performed, and the latter was >95% predictive of CMA, even when intestinal biopsy specimens were normal. Although intestinal permeability studies are often used in clinical research, they are not standard diagnostic modalities in children. However, the data suggest that the standard evaluation for infants who vomit (including pH probe, barium study, or endoscopy) may be inadequate to identify patients allergic to cow’s milk.
Cavataio, Iacono, and colleagues53, 54, 55 have investigated these issues in several prospective, controlled trials, showing that up to 42% of infants under 1 year of age with GER also have CMA. These investigators were the first to identify pH probe characteristics unique to patients with CMA. In this “phasic” pH probe recording, a progressive, gradual, and prolonged fall in pH after milk ingestion occurs, perhaps because of delayed gastric emptying or a functional incompetence of the lower esophageal sphincter as a result of CMA. These findings differ sharply from the typical pH probe findings in infants with “classic” GER, which features a sharp drop in pH and a rapid, random return to baseline caused by transient relaxation of the lower esophageal sphincter.56 The investigators also performed numerous evaluations to screen for CMA in these patients, including skin prick tests, total serum IgE, blood and fecal eosinophils, and quantitative serum IgG to β-lactoglobulin. Assuming values >36% above background as a positive threshold for the anti–β-lactoglobulin assay, they showed 100% sensitivity and 78% specificity for the diagnosis of CMA.55
The data presented by these investigators remain controversial. Their study population may not be representative of classical GER because those with CMA-associated GER also had a higher incidence of concomitant diarrhea or atopic dermatitis,55 thereby potentially overestimating the prevalence of CMA-associated GER. In addition, the significance of circulating antibodies to exogenous protein is debatable because all infants develop antibodies to cow’s milk that gradually decline in the first 2 years of life, even in the absence of allergic symptoms.57 However, allergic patients tend to have higher levels of allergen-specific IgG antibodies,58 so there may be validity in the cutoffs used by these investigators. The phasic pattern on pH probe analysis is extremely compelling but has not been shown by other investigators.59
Further research is needed before solid conclusions about the cause-and-effect relationship of CMA in infants with GER can be made. Technically, primary GER is always a diagnosis of exclusion once obstruction, metabolic disorders, and other inflammatory conditions are ruled out. However, many practitioners are reluctant to perform the invasive testing required to exclude other conditions in the vomiting infant, resorting to formula changes before a clear diagnosis is made. A response to a casein hydrolysate may be indicative of CMA but may also result from altered gastrointestinal motility caused by other properties of the formula. No studies evaluating the response to hypoallergenic formulas in infants with isolated GER, in the absence of underlying small bowel pathology, have been performed.
Eosinophilic gastroenteritis (EG) is characterized by infiltration of the gastric or intestinal walls with eosinophils, peripheral eosinophilia (50%), and absence of vasculitis.60 Other causes of eosinophilia (e.g., parasites, H. pylori, or inflammatory bowel disease) must be ruled out. Patients present with postprandial nausea, abdominal pain, vomiting, diarrhea, protein-losing enteropathy, and weight loss; depending on the depth of infiltration, abdominal bloating, obstruction, and ascites can also develop.61, 62 The diagnosis rests on biopsy, although there may be patchy disease and infiltration may be missed unless multiple biopsies are performed.63 The spectrum of EG was described in a large series by Talley et al. (median age, 36 years).61 Food intolerance or allergy was reported by half of the 23 patients with mucosal disease, but not by any patients with muscle layer or subserosal disease. However, formal studies to determine the role of food allergy were not undertaken. Case reports reflect improvement with elimination diets, but results in adults are generally transient and poor.62 Justinich et al.64, 65, 66 reported complete resolution of EG in a teenage boy who previously required continuous steroid therapy for management through treatment with an elemental formula. Treatment with steroids seems most successful.61 Improvement with sodium cromoglycate has been reported (case reports)67, 68 but is limited,61 and there is a report of improvement with montelukast.69 Controlled trials are lacking for any therapies.
Considering the increased incidence of atopy and reported food intolerance in patients with EG and an element of success for dietary therapy, it seems prudent to consider food allergy in the evaluation of EG. Once a diagnosis is secured, a trial elimination diet may be warranted, primarily in patients with mucosal disease and a history of atopy or food intolerance.61 Current evidence is not convincing for successful treatment of EG with diet alone in most patients, so alternative treatments should be considered (e.g., anti-inflammatory treatments). Clearly, more formal studies of the role of food allergy in this disorder are warranted.
Eosinophilic esophagitis and GER in adults and children
In 1982, Winter et al.70 noted the presence of intraepithelial eosinophils (IEs) in the esophagus of children with proven GER and showed that increased acid exposure directly correlated with the numbers of eosinophils in esophageal epithelium. Since then, the presence of IEs has been considered a central feature in the diagnosis of GER. In adult patients with GER, IEs found on esophageal biopsy have been shown to be the most consistent histologic finding.18, 71 However, there has been increasing evidence that elevated numbers of eosinophils in the esophagus indicate an intrinsic disorder, perhaps a variant of EG. In addition, recent literature has proposed that GER in infants may be caused, in many instances, by allergy to cow’s milk protein, raising the question of whether reflux itself, and not just eosinophilic esophagitis, may be caused, in some cases, by dietary protein sensitization, as discussed above.
EG may diffusely involve the entire gastrointestinal tract or the esophagus, stomach, intestine, or colon separately. Patients with isolated esophageal involvement, eosinophilic gastroenteritis (EE), have a predominance of dysphagia (~85%), caused by either strictures (often proximal) or a variety of manometric abnormalities.72, 73, 74, 75, 76, 77 The latter include diffuse esophageal spasm, increased lower esophageal sphincter pressure, and achalasia. These motor disturbances may result from infiltration of eosinophils into the muscular layers of the intestinal wall or to the elaboration of eosinophil products.78 Although case reports have noted an absence of documented GER by pH probe in these patients, it is not clear that this is true in all patients. A predominance of young males has been noted in several reviews.73, 79, 80
Some investigators have evaluated the number of IEs/high-power field (HPF) to differentiate EE from GER. Attwood et al.78 retrospectively reviewed the histology of esophageal biopsies and identified those patients with >20 IEs/HPF. He compared these patients by pH probe to individuals with documented GER who had a mean number of IEs/HPF of 3.3. The patients with high numbers of IEs were likely to be young and male, and all had normal pH probes. Patients with GER were more likely to have gross abnormalities on endoscopy, including erosions and Barrett’s esophagus, and intraepithelial neutrophils on histology.
A number of other recent studies have attempted to evaluate the meaning of high numbers of IEs in esophageal biopsy specimens. Ruchelli et al.81 retrospectively reviewed a series of 102 children undergoing evaluation for symptoms of GER who showed at least 1 eosinophils/HPF on esophageal biopsy. They compared the number of IEs to the clinical outcome after GER therapy. Patients who failed treatment had a significantly stronger history of allergy (wheezing, rhinitis, urticaria, or atopy) than responders and also had significantly more IEs on biopsy. A threshold of >7 IEs/HPF had a positive predictive value of 85% for determining ultimate failure with medication. Patients in the treatment failure group (12 patients) responded to steroids (8 patients) or an amino acid–based formula (4 patients). The retrospective nature of this study limits its value, as does the fact that 2 patients in the treatment failure group had evidence of diffuse EG. In addition, proton pump inhibitors were not available during this era, so treatment failure may reflect failure to suppress acid adequately rather than imply a different disease. However, the favorable response to diet or anti-inflammatory therapy does suggest a separate disease entity in which a primary allergic or inflammatory disorder may be present. Lee et al.80 retrospectively reviewed esophageal biopsy specimens containing >10 IEs/HPF. Most of these patients were younger than 25, and 1 had diffuse allergic eosinophilic gastroenteritis. There was documentation of GER by either pH probe or barium studies in a majority of patients, suggesting that the presence of high numbers of eosinophils does not exclude a diagnosis of GER. However, response to therapy was not included in the study. In addition to elevated numbers of eosinophils, Justinich et al.82 have noted that individuals with EE, in contrast to those with GER, have increased mucosal mast cells (using special stains) on esophageal biopsy (6.9 vs. 32/HPF); the utility of this finding as a diagnostic method requires further study.
A recent retrospective review by Walsh et al.83 also evaluated children who had failed therapy for GER. All index children had IEs in the esophagus after treatment for GER (mean, 30). Only half these patients had pH probe monitoring, which was normal in all. Patients in this treatment failure group were successfully managed with steroids, elemental diets, or oral cromolyn. Orenstein et al.73 reviewed their experience with 30 pediatric patients with EE and noted that typical endoscopic findings included a granular appearance with furrows or visible rings, typically without ulcers.
Thus, a dense eosinophilic infiltrate, relatively benign endoscopic features, and lack of improvement with GER treatment may denote a primary disorder of esophageal inflammation, likely to respond to anti-inflammatory medications (steroids) rather than antireflux medications. The additional question is: does food allergy induce or contribute to this disorder? Orenstein et al.73 documented positive prick skin tests or RASTs in 13 of 19 children with EE (median, 7 foods). Dietary elimination was undertaken in 12 of the 13 with positive tests. Of 10 who were compliant with the diet, all were believed to benefit with resolution of symptoms. Seven of the patients had concomitant therapies (steroid, 3; antireflux medications, 2; cromolyn, 1; or fundoplication, 1). However, lapses in the diet were accompanied by recurrence of symptoms in the months after diagnosis, despite other therapies. No formal food challenges were performed, and food allergy was not evaluated in those with negative tests for IgE antibody. In a study that specifically addressed the role of food allergy in children with EE, Kelly et al.84 evaluated patients who failed standard GER treatment or fundoplication (6 patients) and who had persistent IEs on esophageal biopsy. These patients were offered treatment with an amino acid–based formula. Eight of 10 patients became symptom-free, and 2 had significant reduction in symptoms within 2–6 weeks after starting the dietary program. Repeat endoscopy showed a decline in median numbers of IEs, from 40 to 0.5. Furthermore, patients underwent open food challenges, and in most cases a select number of foods (typically milk, soy, eggs, peanuts, and wheat) were identified as reproducing symptoms within 1–8 hours of ingestion. Many patients in the study had documented GER before enrollment. Prick skin tests to foods were positive in 6 of 10 patients but correlated poorly with positive challenge results. Interestingly, the patient population included 1 patient with tracheal-esophageal fistula and 2 with cerebral palsy, conditions that are normally associated with a high degree of refractory GER, presumed to be on the basis of abnormal anatomy and motility.85, 86
Taken together, these studies support a role for food allergy in the pathogenesis and treatment of EE, at least in children. It is unknown whether the disease is underdiagnosed in adults who may not have biopsies performed when visual inspection of the esophagus is benign. Evaluation for food allergy is justified, particularly in the subset with indicative histories or positive tests. In addition, the presence of documented GER on pH probe or barium study does not exclude the diagnosis of food allergy. Those patients who fail to improve with standard medication regimens and who have persistent esophagitis after GER therapy may benefit from other therapies before surgery is considered. For EE, steroids have been effective, including case reports of metered-dose inhaled steroids that are swallowed,87 but a trial of an elemental diet may be beneficial in many of these patients. Careful reintroduction of foods may identify specific dietary allergens.
Celiac disease represents an immune response to a food protein (gluten) and therefore may be considered a food allergic disorder.88 However, a full discussion of diagnosis and management is beyond the scope of this report. Ingestion of whole cow’s milk by infants less than 6 months of age may lead to occult blood loss from the gastrointestinal tract and iron deficiency anemia.89 The use of infant formulas generally results in resolution of symptoms. There is limited evidence that infantile colic is associated with food (cow’s milk) allergy in a subset of patients (sometimes on an IgE-mediated basis), but more studies are needed to define the relationship.90, 91, 92 Cow’s milk intolerance has also been suggested as a cause of chronic constipation in older infants and toddlers.93, 94 Investigators have shown the presence of eosinophilic proctitis in children with chronic constipation, resolution of constipation after withdrawal of cow’s milk from the diet (and substitution with soy-based formula), and recurrence upon reintroduction of cow’s milk. However, further studies are needed to confirm these associations. Elemental diets have been shown to induce remission in Crohn’s disease; however, recent meta-analyses have shown that they are inferior to steroids at inducing and maintaining remission despite their popularity in some countries.95, 96, 97 No data have conclusively shown that specific immunologic responses to food alter the course of Crohn’s disease or are responsible for its development. The relationship of irritable bowel syndrome to food allergy has not been systematically studied.98, 99, 100
General diagnostic criteria for food allergy
Early concepts concerning the diagnosis of food allergy incorporated the following tenets: (1) symptoms should follow contact with a food substance that is innocuous to most people, (2) immune mechanisms should be evident in the pathogenesis, (3) other pathogenic mechanisms should be absent, and (4) lesions or functional abnormalities of the gut should be demonstrable.66 Regarding CMA in infants, Goldman et al.101 suggested clinical criteria for diagnosis that included (1) symptoms that subside with elimination of cow’s milk, (2) recurrence of symptoms within 48 hours of milk challenge, and (3) reactions to 3 challenges that are positive and similar in onset, duration, and clinical features. However, these concepts have proven impractical given the myriad of clinical syndromes/symptoms complexes, the heterogeneous immune pathophysiologic causes underlying food allergy, and the severity of symptoms sometimes provoked by oral challenge.
A recent consensus workshop (Workshop on the Classification of Gastrointestinal Diseases of Infants and Children, November 1998, Washington, DC)102 considered a variety of factors in establishing a diagnosis of food allergy: (1) history of an allergic or allergic-like hypersensitivity reaction to a food ingestion; (2) exclusion of anatomic, functional, metabolic, or infectious causes; (3) pathologic findings consistent with an allergic cause (usually eosinophilia); (4) confirmation of a relationship between the ingestion of specific food to the development of symptoms by clinical challenges or repeated, inadvertent exposures; (5) evidence of the food-specific IgE antibody in settings of IgE-mediated disease; (6) failure to respond to conventional therapies aimed at anatomic, functional, metabolic, or infectious causes; (7) improvement in symptoms with elimination of the causal dietary proteins; (8) clinical response to treatments of allergic inflammation (i.e., corticosteroids); (9) similarities to clinical syndromes either proven or presumed to be caused by immunologic mechanisms; and (10) lack of other explanations for the clinical allergic-like reaction. These elements take into consideration the variety of clinical manifestations of food-allergic disorders and the overlap with nonfood allergic disorders. Consequently, one single recommendation cannot be made for diagnosing gastrointestinal food allergy, and proof of underlying immunologic mechanisms is lacking for most of the described disorders, except for those mediated by food-specific IgE antibodies.
Assimilation of these elements with knowledge about the particular gastrointestinal diseases/symptom complexes, associated features (i.e., atopic disease), and the timing of symptom onset (acute vs. chronic) is essential in evaluating the role of food allergy in particular patients with gastrointestinal disorders. In addition, it is clear that in many disorders, a lack of response to treatments other than food elimination, and even a successful response to medical or surgical treatment, does not necessarily exclude food allergy as an etiologic factor in the condition.
As outlined above, infants and children are more likely to have food allergic disorders than adults. Acute gastrointestinal reactions, such as vomiting and diarrhea, occurring shortly after a particular food is ingested in a patient with IgE antibodies to the food in question, are the most likely to be food allergies and are easiest to evaluate. However, such cases are in the minority.4, 31, 34, 91, 101 Food allergy is more likely to induce gastrointestinal symptoms when other disorders associated with food allergy are present, such as atopic dermatitis, acute reactions to foods, asthma, or family history of atopy.5, 25, 27, 34, 39, 41, 101, 103 Finally, particular disorders/symptom complexes, as outlined above, may be caused by food allergy.
Specific IgE antibody
In the evaluation of IgE-mediated food allergy, specific tests can help to identify or exclude responsible foods. One method to determine the presence of specific IgE antibody is the use of prick or puncture skin tests. A device, such as a bifurcated needle or lancet, is used to puncture the skin through a glycerinated extract of a food and appropriate positive (histamine) and negative (saline-glycerine) controls. A wheal-and-flare response at the site indicates the presence of food-specific IgE antibodies (a wheal >3 mm is considered positive). Negative skin prick tests are the most diagnostic because the negative predictive value of the negative skin test is excellent (>95%).104, 105 Unfortunately, the positive predictive value of a positive test is slightly <50%.104, 105 Thus, a positive skin test in isolation cannot be considered proof of clinically relevant hypersensitivity. Intradermal skin testing with food extracts is contraindicated because they give an even higher false-positive rate and have been associated with systemic reactions, including fatal anaphylactic reactions.105
In vitro tests for a specific IgE RAST are also helpful in the evaluation of IgE-mediated food allergy.106 Unlike skin tests, RASTs can be used while the patient is taking antihistamines and do not depend on having an area of rash-free skin for testing. Like skin tests, a negative result is very reliable in ruling out an IgE-mediated reaction to a particular food, but a positive result has low specificity.
In addition to the high false-positive rate of tests for food-specific IgE antibodies, several other issues complicate the interpretation of these tests. It is not uncommon for patients to have positive skin tests and RASTs to several members of a botanical family or animal species. This usually represents immunologic cross-reactivity but frequently does not represent clinical cross-reactivity. For example, most peanut-allergic patients will have positive skin tests to at least a few of the other members of the legume family (e.g., peas, soybeans, or green beans) but have no clinical symptoms after ingestion.107 Confirmation with oral challenges, if allergy is not apparent by history, would be required. Consequently, the foods selected for testing should be limited to include only those suspected of provoking symptoms, thus decreasing the likelihood of false-positive skin tests that inappropriately lead to questions about foods that have been previously tolerated. An additional issue to consider is that the protein in commercial extracts available for testing many fruits and vegetables is prone to degradation. In testing such foods, use of the fresh food is required to obtain more reliable results.108
In evaluating gastrointestinal food allergy, tests for specific IgE antibodies are more likely to be positive in (1) syndromes that are acute in onset after ingestion of the causal protein and (2) patients with other manifestations of atopic disease. Although confirming that a disorder is the result of a food allergy may ultimately require an oral food challenge (or convincing history of reactivity), it is often helpful for the clinician to evaluate patients for food-specific IgE antibody. When a skin test/RAST-positive food is eliminated from the diet for several weeks and then readministered, it can elicit a more severe, acute reaction than seen when ingested on a regular basis. Consequently, such challenges are often best done under physician supervision with treatment for acute, severe reactions immediately available. Except for the enterocolitis syndrome, addition of prick skin test/RAST-negative foods should not elicit life-threatening reactions.
Other immunologic tests
A variety of immunologic tests have been evaluated in the assessment of food allergy in gastrointestinal diseases. Serum IgG antibodies to foods are the normal consequence of exposure to foods in the diet. Although some studies have shown that cow’s milk allergic individuals may have higher cow’s milk–specific titers, this is not a consistent finding, and the diagnostic value of this test has been debated.55, 57, 58, 109, 110, 111, 112, 113, 114 Because most of the gastrointestinal food allergies are not mediated by IgE antibodies, tests for cellular immunity, such as lymphocyte proliferation assays, have been investigated, but no such tests with acceptable sensitivity/specificity ratios have been found.10, 115, 116, 117, 118, 119 A number of other laboratory parameters, such as determination of eosinophil by-products in biopsy specimens or fecal samples, are under investigation. Tests that are clearly not helpful and considered unproved and experimental should not be used: measurement of food-specific IgG4 antibodies, provocation neutralization (use of drops under the tongue or injected into the skin to elicit and then reverse reactions), cytotoxicity (addition of food to whole blood observed under the microscope), applied kinesiology (muscle-strength testing), and other unproved methods.120
Biopsy, functional studies, ancillary tests
The role of biopsy has been reviewed under specific disorders. Clearly, endoscopy and biopsy are integral components necessary to establish the diagnosis, in some settings, and to confirm allergic reactivity (i.e., villus blunting in enteropathy syndrome and eosinophilic infiltration in EG or EE). Tests for malabsorption or acid reflux (pH probes) may play a similar supportive role in some settings. As indicated, stool samples for occult blood are also helpful adjuncts. However, none of these tests are specific tests for food allergy.
The first step in determining whether food allergy is causing symptoms is to eliminate all forms of the suspected food and observe for resolution of symptoms. There are 3 types of elimination diets: (1) elimination of 1 or several foods suspected of provoking symptoms, or the food-specific elimination diet; (2) elimination of all but a defined group of “allowed” foods, or the oligoantigenic diet; and (3) use of an amino acid–based formula, or the elemental diet. The type of elimination diet used will depend on the clinical situation being evaluated, the age of the patient, and the results of tests for food-specific IgE antibody. The first type of diet, which involves the elimination of one or several foods, may be the obvious course of action when an isolated food ingestion provokes a sudden acute reaction and there is a positive test for IgE to the food. This would also represent a therapeutic intervention. When evaluating chronic symptoms, as occurs for most of the gastrointestinal manifestations of food allergy, it is usually not apparent that one or a few foods are causal, so a food-specific elimination diet may not be practical.
The second type of elimination diet, the oligoantigenic diet, consists of eliminating a large number of foods suspected of provoking a chronic problem (usually including those that commonly provoke food-allergic reactions as described above) and giving a list of “allowed foods.” This diet may be more practical when there are chronic symptoms along with chronic ingestion of a large number of foods, including those more likely to provoke allergic reactions. An example of such a diet may be one that includes lamb, rice, corn, cooked apple, broccoli, asparagus, spinach, lettuce, sweet potato, salt, sugar, vinegar, and olive oil. Individualization for this type of elimination diet is almost always needed. The advantage of this diet is that a nutritionally balanced, palatable diet is maintained while most of the likely causal foods are removed. The primary disadvantage is that, if symptoms persist, the cause could still be attributed to foods left in the diet (e.g., rice or lamb).
The third type of elimination diet is an elemental diet in which calories are obtained from an amino acid–based formula. A variation including a few foods is likely to be tolerated, but again, this adds the possibility that persistent symptoms are caused by these foods. This diet is generally difficult to maintain in patients beyond infancy. In extreme cases, nasogastric feeding of the amino acid–based formula can be achieved, although some patients can tolerate the taste of these preparations with the use of flavoring agents provided by the manufacturers. This diet may be required when the less restrictive diets fail to resolve symptoms, but suspicion for food-related illness remains high. Elemental diets are generally required in disorders associated with multiple food allergies, such as EG.
When using any of these diets, specific information must be carefully reviewed to ensure adherence to the diet. It is common for families to make errors. In a milk-free diet, for example, patients must be instructed not only to avoid all milk products, but also to read ingredient labels for key words that may indicate the presence of cow’s milk protein. Terms such as casein, caseinate, whey, and lactalbumin, for example, signify the presence of cow’s milk protein. Patients must also be made aware that the food protein, as opposed to sugar or fat, is the ingredient being eliminated. For example, lactose-free milk contains cow’s milk protein, and many egg substitutes contain chicken egg proteins.
Contamination with the food protein being eliminated can also be a problem. For example, shared kitchen utensils or foods processed on shared industrial equipment can result in cross-contamination. Hidden ingredients can also cause a problem. For example, egg white may be used to glaze pretzels, or peanut butter may be used as a “secret ingredient” in sauces. When multiple foods are eliminated from the diet, it is prudent to enlist the aid of a dietitian in formulating a nutritionally balanced diet.
Elimination diets can be the first step in the evaluation of food allergy for any cause. Failure to elicit resolution of symptoms would rule out food allergy, although successful dietary management may not prove that a food allergy was causal.
Physician-supervised oral food challenges are required for the diagnosis of food-allergic disease in several settings. In general, when several foods are under consideration as a cause of symptoms, tests for food-specific IgE are positive, and elimination has resulted in resolution of symptoms, oral challenge testing for each food eliminated is indicated to diagnose specific sensitivities and allow expansion of the diet. In the case of an acute anaphylactic-type reaction lacking evidence of food-specific IgE for a food highly suspected of provoking the reaction, a physician-supervised challenge is indicated to reintroduce the food safely in case there is a false-negative skin/RAST test. If suspicion concerning a particular food remains high despite elimination without resolution of symptoms, challenges may be needed to clarify the issue. If tests for specific IgE antibodies are not relevant to the disorder, oral challenges are often the only means of diagnosis. This is the case for most of the gastrointestinal hypersensitivity reactions. Oral challenges are also required to determine when clinical tolerance has developed.
Oral challenges may be optional or contraindicated in some settings. Severe anaphylaxis after the isolated ingestion of a food, with evidence of specific IgE antibody to the causal food, is one clear example of a relative contraindication for oral challenge (although this, too, is individualized because follow-up challenge for determination of resolution of allergy may be appropriate in some settings). If the food being eliminated is not a major part of the diet, then challenge is not usually warranted. If several members of a food family are being eliminated, but the food family is not a major part of the diet (e.g., tree nuts), these same rules may apply.
In most circumstances, physician-supervised oral challenges are preferred, but there are exceptions for practical purposes. In general, whenever there is a remote potential for an acute or severe reaction, physician supervision is mandatory. This decision for a supervised challenge includes, but is not limited to, a history of prior significant or acute reactions or positive tests for IgE to the food in question. In considering this issue, a distinction should also be made between “challenging” a food and “adding a food back to the diet.” For example, if many foods have been eliminated for a chronic, presumed non–IgE-mediated disease and acute reactions are not an issue, adding the previously tolerated food back to the diet at home should not cause a problem. In a similar manner, patients with a chronic disorder that responded to an elimination diet may have foods added back to their diet without physician supervision if symptoms were not severe and not IgE-mediated. This is undertaken by adding one new food every 5 days while monitoring for recurrence of symptoms.
For oral food challenges performed under physician supervision, several issues must be taken into consideration. Oral challenges can elicit severe anaphylactic reactions, so the physician must be comfortable with this potential for reaction and be prepared with emergency medications and equipment to treat such a reaction promptly. Medications that should be available (in premeasured doses based on weight) include epinephrine, antihistamines, corticosteroids, inhaled beta-agonists, type-2 histamine blockers (cimetidine), activated charcoal, and intravenous fluid (volume expanders such as normal saline or colloids). Performing the challenge in a hospital setting may be prudent if the challenge is considered “high risk” (positive test for food-specific IgE antibodies, previous severe reaction, asthmatic patient, or enterocolitis syndrome). In high-risk challenges, intravenous access should be placed before beginning the challenge. Patients should avoid the suspected foods for at least 2 weeks, discontinue antihistamines according to the elimination half-life of the drug, and reduce asthma medications as much as possible before undertaking the challenge. The patient should be examined carefully before challenge to confirm that they are not already having chronic symptoms and to establish their “baseline.”
Challenges can be done “openly,” with the patient ingesting the food; “single-blind,” with the food masked and the patient unaware if he or she is receiving the test food; or as double-blind placebo-controlled food challenges, in which neither patient nor physician knows which challenges contain the food being tested. In all of these challenges, the food is given in gradually increasing amounts that may be individualized both in dose and timing, depending on the patient’s history. For most IgE-mediated reactions,121, 122 8–10 g dry food or 100 mL wet food (double amount for meat or fish) is divided and given at 10–15-minute intervals for about 90 minutes (dividing the total dose into servings of 1%, 2%, 5%, 10%, 20%, 20%, 20%, and 22% of the total). This is followed by a larger, meal-size portion of food a few hours later. However, the amount given and the timing between administration require adjustment, depending on the history or illness. For example, delayed-onset disease (enteropathy) may require several days of ingestion. For milk challenges, a lactose-free substance is preferred to exclude mislabeling a lactase deficiency.
Symptoms are recorded and frequent assessments made during the challenge. Challenges are terminated when a reaction becomes apparent, and emergency medications and intravenous fluids are given, if needed. Objective observations for a positive endpoint (vomiting or diarrhea) are preferred. Depending on the pathophysiology of the illness, symptoms outside the gastrointestinal tract may be elicited (respiratory, cardiovascular, and skin symptoms). In some settings, ancillary tests, such as occult fecal blood, endoscopy, or pH probe, may be helpful.
FPIES deserves special precautions and a slightly different approach to challenge.31, 41 When severe, particularly with refeeding after a period of elimination, lethargy, dehydration, acidosis, and hypotension may occur.32, 33, 40 Food challenges for this non–IgE-mediated syndrome are typically performed with 0.15–0.6 g/kg of the causal protein, usually cow’s milk or soy. Reactions of profuse vomiting and diarrhea typically begin 2–6 hours after ingestion and are accompanied by a rise in the absolute neutrophil count of >3500 cells/mm3. Given these severe symptoms and the potential for shock, intravenous access must be obtained in advance, and the challenge is best performed in a hospital setting. Intravenous fluids and corticosteroids may be needed for treatment of reactions.
Open challenges can be very useful, particularly in eliminating a food as a potential cause of symptoms. They take no significant preparation, and patients can be asked to bring the food with them to the office. Open challenges are best performed to exclude a food allergy and when there is little chance that the patient’s belief would bias results. Thus, open challenges are most useful for confirming negative skin test results in the setting of a potential reaction that was not severe, unless the family or patient was strongly convinced it was causal. Similarly, objective positive responses, such as vomiting and diarrhea, are helpful in reliable patients. When an open challenge is suspected to be falsely positive, a follow-up double-blind, placebo-controlled food challenge is needed.
Single-blind challenges are helpful in reducing patient bias during food challenges, but double-blind placebo-controlled food challenges are considered the gold standard for diagnosing food allergy because all bias can be eliminated.103, 104, 122 The procedure is labor intensive but can be modified for an office setting.122 Graded doses of either a challenge food or a placebo are administered. The challenge food is hidden either in another food or in opaque capsules. Depending on the particular disorder, the interval between dose administration must be adjusted. The assistance of a third party is needed to prepare the challenges. A coin flip can be used to randomize the order of administration. This type of challenge is mandatory when symptoms have been subjective, such as abdominal pain or poor appetite. It is also the preferred type of challenge for research studies. When multiple foods are suspected, single-blind challenges may be used to screen for reactivity. Negative challenges are always confirmed with open feeding of a larger, meal-sized portion of the food, also under physician supervision. Unprocessed foods are preferred for all challenges.
Conclusions and clinical recommendations
Food allergy should be considered in patients with characteristic signs and symptoms, suggestive immunologic responses or biopsy findings, and in whom other causes are unidentified (or who fail therapy). Once considered, the diagnosis of food allergy rests on directed laboratory tests, responses to food challenge, and food exclusion.123, 124 The literature indicates that food allergy is rarely an issue for adults, so expensive evaluations should be avoided unless suspicion (usually attained by history) is high. In contrast, food allergy is more commonly associated with gastrointestinal disorders in infants and young children. A formal cost analysis of the evaluation of food allergy is not possible. Judicious use of tests, alternative diets, and appropriate re-evaluation should limit unnecessary health care costs.
Even without performing adjunctive laboratory tests, pediatricians (and families) commonly undertake formula changes as a test of intolerance or allergy. There have been no specific guidelines concerning these formula changes. It is helpful to know that a small proportion of infants with IgE-mediated CMA (14%) react to soy. In contrast, those with non–IgE-mediated CMA are frequently reactive to soy protein (>50%125). For these infants, a switch to extensively hydrolyzed cow’s milk–based formula usually resolves the symptoms.126 For a small proportion of infants with symptoms that continue on hydrolysate, an amino acid–based formula may be required.23, 42, 126 Breast-feeding is clearly cost-effective compared with infant formula,127 but maternally ingested protein can elicit allergic symptoms in the breast-fed infant.128 Maternal dietary manipulation can be undertaken for treatment in breast-fed infants, but it may be difficult with multiple food–allergic infants, and substitution with infant formulas may be needed.129 Evaluation for resolution of allergy is mandatory to limit the use of expensive alternative formula, and even those requiring hypoallergenic formula usually become tolerant of foods within 1–2 years.130
Suggestions for future research
Although the etiologic role of food allergy is clear for IgE-mediated disorders (i.e., celiac disease, proctocolitis, enteropathy, and enterocolitis), more research is needed to define the role of food allergy in EE, EG, and other disorders reported to be associated with food allergies. Better diagnostic methods (laboratory methods) are sorely needed for all of these disorders to efficiently determine specific allergies and to monitor for resolution. Evaluation of the cost-effectiveness of the evaluation and treatment of food allergy is also needed. Basic research on the mechanisms of these disorders is under way.
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