Definitions and Epidemiology
Food allergy is a common problem in the pediatric age group, one that has numerous manifestations and touches on many organ systems. As such, food allergy is often first seen and managed by the generalist such as the pediatrician or family practitioner. However, various aspects of food allergy may also necessitate the involvement of a subspecialist. For the purposes of this chapter, we will focus on the aspects of food allergy and intolerance that involve the gastrointestinal tract and may require the assistance of a gastroenterologist.
Immune-mediated food reactions are typical (IgE-mediated or type 1) food allergy as well as several types of food reactions that involve either mixed (IgE and non-IgE) or delayed (non-IgE) hypersensitivity. GI manifestations of type 1 food allergy include the oral allergy syndrome (OAS) and immediate hypersensitivity reactions. From this point forward, the term food allergy will refer to immune-mediated food reactions, with a particular emphasis on the gastrointestinal manifestations of each of these reactions.
Type I (IgE-mediated) immediate hypersensitivity reactions to foods are most common in young children, with 50% of these reactions occurring in the first year of life. The majority are reactions to cow’s milk or to soy protein from infant formulas.1 Other food allergies begin to predominate in older children, including egg, fish, peanut, and wheat. Together with milk and soy, these account for more than 90% of food allergy in children.2
There are several gastrointestinal illnesses that manifest as a result of mixed and non-IgE allergies. Some, such as gastroesophageal reflux (GER), infantile colic, constipation, and diarrhea, are multifactorial illnesses, in which food allergy may play a prominent role in a proportion of patients with refractory symptoms. Others, such as infantile allergic proctocolitis (AP), eosinophilic esophagitis (EoE), and in some cases eosinophilic gastroenteritis (EoG), are disorders where food allergy has been demonstrated as the main (if not only) causative factor.
The gastrointestinal tract plays a major role in the development of oral tolerance to foods. Through the process of endocytosis by the enterocyte, food antigens are generally degraded into non-antigenic proteins.3,4 Although the gastrointestinal tract serves as an efficient barrier to ingested food antigens, this barrier may not be mature for the first few months of life.5 As a result, ingested antigens may have an increased propensity for being presented intact to the immune system. These intact antigens have the potential for stimulating the immune system, and driving an inappropriate response directed at the gastrointestinal tract.
With IgE-mediated food allergy, the rapid onset of GI symptoms after food ingestion correlates highly with positive IgE–RAST or skin prick tests to the offending antigen, demonstrating that these reactions are related to typical type 1 hypersensitivity. On the other hand, in patients with OAS, symptoms relate to cross-reaction between similar epitopes on certain pollens and certain fruits and vegatables.6
EoE and gastroenteritis are thought to arise from the interaction of genetic and environmental factors. Of note, approximately 10% of individuals with one of these disorders have a family history in an immediate family member.7 In addition, there is evidence for the role of allergy in the etiology of these conditions, including the observations that up to 75% of patients are atopic8,9 and that an allergen-free diet can sometimes reverse disease activity.8–10 Interestingly, only a minority of individuals with eosinophilic gastroenteropathies have food-induced anaphylaxis,11 as evidence that these are not pure IgE-mediated food allergies.
Oral allergy syndrome may begin in childhood or may be adult onset. It is manifested by a combination of oral itching, burning, swelling, and erythema, but rarely results in systemic symptoms.6Table 17–1 outlines the common foods and pollens that cause OAS.
|Pollen||Potential Cross-reactive Foods|
|Ragweed||Bananas, melons (watermelon, cantaloupe, honeydew) zucchini, cucumber, dandelions, chamomile tea|
|Birch||Apples, pears, peaches, apricots, cherries, plums, nectarines, prunes, kiwi, carrots, celery, potatoes, peppers, fennel, parsley, coriander, parsnips, hazelnuts, almonds, walnuts|
|Grass||Peaches, celery, melons, tomatoes, oranges|
|Mugwort||Celery, apple, kiwi, peanut, fennel, carrots, parsley, coriander, sunflower, peppers|
|Alder||Celery, pears, apples, almonds, cherries, hazelnuts, peaches, parsley|
|Latex||Bananas, avocado, kiwi, chestnut, papaya|
Immediate GI hypersensitivity usually occurs in the setting of a systemic allergic reaction such as anaphylaxis and typically involves a combination of nausea, abdominal pain, vomiting, and diarrhea. Onset may be anywhere from seconds to several hours after food ingestion. Resolution of gastrointestinal symptoms may also be rapid, and occasionally forceful vomiting induces complete resolution of symptoms after the stomach has been completely emptied of the inciting antigen.12
AP, also known as allergic colitis or milk–protein proctocolitis, has been recognized as one of the most common etiologies of rectal bleeding in infants.13,14 This disorder is characterized by the onset of rectal bleeding, generally in children less than 2 months of age.
Diarrhea, rectal bleeding, and increased mucus production are the typical symptoms seen in patients who present with AP.14,15 The typical infant with AP is well appearing with no constitutional symptoms. Rectal bleeding begins gradually, initially appearing as small flecks of blood. Usually, increased stool frequency occurs, accompanied by water loss or mucus streaks. The development of irritability or straining with stools is also common and can falsely lead to the initial diagnosis of anal fissuring. Atopic symptoms, such as eczema and reactive airway disease, may be associated. Continued exposure to the inciting antigen causes increased bleeding and may, on rare occasions, cause anemia and poor weight gain. Despite the progression of symptoms, the infants generally appear to be well. Other manifestations of gastrointestinal tract inflammation, such as vomiting, abdominal distention, or weight loss, almost never occur.
EoE, also known as allergic esophagitis, has come to the forefront in individuals previously suspected as having severe, chronic gastroesophageal reflux disease (GERD). EoE is a disease of children and adults characterized by an isolated, severe eosinophilic infiltration of the esophagus manifested by GER-like symptoms, such as regurgitation, epigastric and chest pain, vomiting, heartburn, feeding difficulties, and dysphagia.16 Classically, the presentation is that of GER, refractory to treatment with acid suppression therapy. Younger children tend to present with more non-specific symptoms such as abdominal pain and feeding refusal, while older children and adults often present with dysphagia and esophageal food impactions. Uncommon symptoms include growth failure, hematemesis, globus, and water brash (Table 17–2).
|Eosinophilic Esophagitis||Gastroesophageal Reflux|
|Symptoms||Nausea, vomiting, epigastric pain, dysphagia||Nausea, vomiting, epigastric pain, dysphagia|
|Endoscopic findings||Esophageal furrows, rings, white specks||Esophageal ulceration, erythema|
|Histologic findings||Usually 20 or more eosinophils/HPF||Usually 5 or less eosinophils/HPF|
|Esophageal strictures||Mid-esophagus if present||Distal esophagus if present|
|pH studies||Essentially normal, with some increased frequency of reflux episodes||Abnormal|
|Peripheral eosinophils||Usually increased||Usually normal|
|Serum IgE||Usually increased||Usually normal|
|Atopic history||Increased rates of atopic disease||Baseline rates of atopic disease|
|Family history||Increased family history of atopic disease||Baseline family rates of atopic disease|
|Response to acid blockade||Partially responsive symptoms; histologic findings unresponsive||Symptoms and histologic findings respond|
|Response to fundoplication||Symptoms and histologic findings persist||Symptoms and histologic findings respond|
|Response to corticosteroids||Symptoms and histologic findings respond||Symptoms and histologic findings persist|
|Response to elimination diet||Symptoms and histologic findings respond||Symptoms and histologic findings persist|
The clinical features of EoE may evolve over years. Symptoms such as abdominal pain and heartburn occur regularly; however, patients with vomiting or dysphagia may display these symptoms sporadically, complaining only once or twice a month. Although the use of acid-suppressing medication often improves the patient’s symptoms, it does not eliminate the symptoms or change the abnormal esophageal histology. Approximately 50% of affected children also exhibit other allergic signs and symptoms, including bronchospasm, allergic rhinitis, and eczema. Frequently, there is a strong family history of food allergies or other allergic disorders.
EoG is a general term that describes a constellation of symptoms attributable to the gastrointestinal tract, in combination with pathologic infiltration by eosinophils. This group includes eosinophilic gastritis, gastroenteritis, and enteritis. There are no strict diagnostic criteria for this disorder and it has been largely delineated by multiple case reports and series. A combination of gastrointestinal complaints with supportive histologic findings is sufficient to make the diagnosis. These conditions are grouped together under the term EoG for the discussion here, though it is likely that they are distinct entities in most patients.
The most common symptoms of EoG include colicky abdominal pain, bloating, diarrhea, weight loss, dysphagia, and vomiting.17,18 In addition, up to 50% have a past or family history of atopy.14 Features of severe disease include gastrointestinal bleeding, iron deficiency anemia, protein-losing enteropathy (hypoalbuminemia), and growth failure.17 Approximately 75% of affected patients have an elevated blood eosinophilia.19 Males are more commonly affected than females. Rarely, ascites can occur.19,20
In an infant, EoG may present in a manner similar to hypertrophic pyloric stenosis, with progressive vomiting, dehydration, electrolyte abnormalities, and thickening of the gastric outlet.21,22 When an infant presents with this constellation of symptoms, in addition to atopic symptoms such as eczema and reactive airway disease, an elevated eosinophil count, or a strong family history of atopic disease, EoG should be considered in the differential diagnosis before surgical intervention if possible.
GER is a common complaint among infants, children, and adults. Up to two-thirds of 4-month-old infants experience regurgitation on a daily basis,30 with other complaints such as forceful vomiting, arching, irritability, and feeding refusal occurring to varying degrees. Furthermore, many infants and children may experience GER without the presence of any overt signs or symptoms. Most cases of GER are not attributable to a specific underlying cause; however, one of the leading identifiable causes of GER in this population is food allergy.31,32
Relatively recently, the association between GER and cow’s milk allergy (CMA) was prospectively investigated.32 In a 3-year prospective study, infants with symptoms compatible with GER underwent pH monitoring and endoscopy to confirm the presence of GER. Patients with a reflux index (percentage of time with acid reflux) greater than 5% and the presence of esophagitis were considered to have GER. The presence of CMA in these patients was assessed using skin prick tests, the presence of eosinophils in fecal mucus, nasal mucus, or peripheral blood, and by circulating levels of anti-beta-lactoglobulin IgG. Patients who had positive assays for CMA and GER were placed on a cow’s milk restricted diet with a protein hydrolysate formula. After 3 months, a double-blind cow’s milk challenge was performed to confirm the diagnosis of CMA.
This stringent method of diagnosing both GER and CMA revealed a surprisingly high prevalence (42%) of patients with GER who also had CMA. Further, this author group went on to show that 14 of 47 patients (30%) had GER that was attributable to the CMA itself, based on resolution of symptoms on restricted diet followed by return of symptoms when re-challenged.
Whether cow’s milk or other food allergies are responsible for such a high proportion of GER in all populations remains to be seen; however, these results imply that refractory cases of GER warrant consideration of food allergy as a contributing factor.
Infantile colic is a term that is generally used to describe acute self-limited episodes of irritability (presumably due to abdominal pain) that occur in otherwise healthy infants in the first several months of life.33 Although labeling an infant as having “colic” implies there is no organic disease responsible, a subset of infants diagnosed with colic will have an underlying organic cause. Food allergies, and specifically CMA, have been highly implicated in the organic etiologies of infantile colic.
In a trial of 70 formula-fed infants, 50 (71%) had resolution of colic symptoms when cow’s milk protein was removed from the diet, with 100% relapse rate after two successive reintroductions of the protein.34 Similarly, in a double-blind crossover study, CMA was implicated in 24 of 27 infants with colic with significant reductions in daily crying when cow’s milk protein was removed from the diet,35 with worsening of symptoms when whey was reintroduced into the diet in a blinded fashion.
Traditionally, changing the infant’s formula is a common way of dealing with colic; often several formula changes are made (e.g., from cow’s milk based to soy based to hydrolyzed protein). It is often unclear, however, whether the formula change is responsible for the eventual resolution of symptoms, as colic by definition begins to resolve by 4–5 months of age.
The presence of diarrhea in the context of food allergies can be multifactorial. As discussed in previous sections, EoG and AP may both lead to intestinal mucosal damage and subsequent diarrhea. However, food allergy may also result in diarrhea in the absence of mucosal damage or eosinophilic infiltration.
Gastrointestinal symptoms, in particular diarrhea, are commonly seen among children with atopic eczema36,37; avoidance of particular foods in these patients will alleviate the symptoms.37 In patients with GI symptoms related to milk ingestion (confirmed by double-blind challenge), the instillation of milk into the intestinal lumen resulted in increased production of histamine and eosinophil cationic protein within 20 minutes.38 Albumin concentration in the intestine also increased, suggesting increased gut permeability and leakage; none of these findings were seen in normal controls.
Animal models suggest that food allergy may also increase intestinal motility, which in turn may lead to diarrhea.39 Increased intestinal mast cell counts have been seen in subjects with increased intestinal motility.40 However, diarrhea in relation to food allergy is almost certainly a multifactorial event that may involve other processes such as secondary carbohydrate malabsorption or overingestion of non-absorbable sugars.
Constipation is a common problem among infants and children, and although often short-lived or self-limited, a substantial proportion may have symptoms that persist for 6 months or more.41 It has long been suggested that cow’s milk plays a role in the development of chronic constipation,42 and there is evidence that CMA is a causative factor. One of the most compelling studies involved a blinded crossover study of cow’s milk restriction in children with chronic constipation.43 In this trial, 65 children with chronic constipation (all of whom received cow’s milk in their regular diet) were randomized to receive either cow’s milk or soy milk for 15 days, followed by a washout period and reversal of the previous diet. Sixty-eight percent of the children had improvement in their constipation while taking soy milk, while none had improvement on cow’s milk. Re-challenging the responders with cow’s milk resulted in return of constipation. Evidence of CMA was based on higher frequencies of co-existent rhinitis, dermatitis, and bronchospasm in responders, as well as increased likelihood of elevated IgE to cow’s milk antigens and inflammatory cells on rectal biopsy. A subsequent study revealed further evidence of the causative nature of CMA in constipation.44
The differential diagnosis of the various disorders outlined above depends on several factors including clinical presentation, associated symptoms, and timing with regard to food ingestion. See Figure 17–1. First and foremost, it is important to differentiate between food allergy and other types of food reaction.
Toxic reactions do not involve the immune system, but may present in a fashion similar to immune-mediated food reactions. For example, scombroid is a food-related illness following the ingestion of improperly stored fish. When certain fish are not properly refrigerated, bacterial production of biogenic amines, in particular histamine, can occur, leading to markedly increased levels. Ingestion leads to histamine-mediated reactions in the GI tract including flushing, nausea, vomiting, and diarrhea.
In addition to toxic reactions, other non-immune-mediated food intolerances may produce gastrointestinal symptoms. Lactose intolerance from congenital or acquired deficiency of the intestinal brush border enzyme lactase may lead to symptoms of abdominal pain, distention, gas, bloating, and diarrhea following the ingestion of lactose. Similar syndromes can be seen with the malabsorption of other carbohydrates such as sucrose, fructose, trehalose, and stachyose as well as sugar alcohols such as sorbitol. Celiac disease represents an immune-mediated food reaction, but is not considered to be an allergy.
Because many of the manifestations of GI allergy, such as GER, abdominal pain, vomiting, diarrhea, and rectal bleeding, are non-specific, other common causes of each of these must be considered within the differential diagnosis (Table 17–3). Additionally, EoE and gastroenteritis must be differentiated from other causes of tissue eosinophilia such as parasitic infection and inflammatory conditions such as Crohn’s disease (Table 17–4).
|The differential diagnosis is broad prior to performing the diagnostic test for eosinophilic esophagitis. After endoscopy the differential decreases significantly|
|Differential diagnosis at presentation|
|Gastroesophageal reflux disease (GERD)|
|Peptic ulcer disease|
|Infection, that is, Helicobacter pylori|
|Inflammatory bowel disease|
|Connective tissue disease|
|Differential diagnosis after biopsy-proven eosinophilia in the esophagus|
|Parasitic or fungal infections|
|Inflammatory bowel disease|
|Chronic granulomatous disease|
|Oral gold therapy|
|Idiopathic hypereosinophilic syndrome|
|Inflammatory bowel disease (Crohn’s disease)|
|Oral gold therapy|
|Idiopathic hypereosinophilic syndrome|
|Inflammatory bowel disease (Crohn’s or ulcerative colitis)|
See Figure 17–2 for an algorithm outlining diagnostic thought process.