Etiology

EoE is caused by an abnormal immunologic response to specific antigens. In the vast majority of cases the antigens responsible are food antigens, although there appears to be a contribution from other environmental antigens in certain individuals. While several studies have documented resolution of EoE with strict avoidance of food antigens, in 1995 Kelly et al published the seminal paper on EoE. Because the suspected etiology was an abnormal immunologic response to specific unidentifiable food antigens, each patient was treated with a strict elimination diet which included an amino acid based formula. Patients were also allowed clear liquids, corn and apples. Seventeen patients were initially offered a dietary elimination trial; 10 patients adhered to the protocol. The initial trial was determined by a history of anaphylaxis to specific foods and abnormal skin testing. These patients were subsequently placed on a strict diet consisting of an amino acid based formula for a median of 17 weeks. Symptomatic improvement was seen within an average of 3 weeks after the introduction of the elemental diet (resolution in 8 patients, improvement in 2). In addition, all 10 patients demonstrated a significant improvement in esophageal eosinophilia. All patients reverted to previous symptoms upon reintroduction of foods.

While an exact explanation for this type of response was not determined, Kelly et al suggested an immunologic basis, secondary to a delayed hypersensitivity or a cell-mediated hypersensitivity response, as the cause for EoE. Spergel et al demonstrated that foods that cause EoE do not do so through immediate hypersensitivity reactions. By using a combination of traditional skin prick testing and a lesser used technique of atopy patch testing, they established that a delayed cellular mediated allergic response may be responsible for many cases of EoE. Further supporting a delayed type response, CD8 ⁺ lymphocytes have been identified as the predominant T cell within the squamous epithelium of patients diagnosed with EoE.

A link between EoE and atopy has been established. It is these links between atopy and EoE that originally suggested that food allergies play a role in the pathogenesis of this disease. The role of food allergy was confirmed when patients improved on elemental diets. Elimination of the responsible food usually does not lead to rapid resolution of the symptoms. Rather, improvement of symptoms occurs approximately 1 to 2 weeks after the removal of the causative antigen. Also, in patients with EoE, symptoms do not always occur immediately after reintroduction to the foods. It may take several days for symptoms to develop, suggesting either a mixed IgE and T cell mediated allergic response or strictly a T cell delayed mechanism in the pathogenesis of this disease. While both IgE and T cell mediated reactions have been identified as possible causative factors, T cell mediated reactions seem to be the predominant mechanism of disease.

Several authors have suggested that aeroallergens may contribute to the development of EoE. Mishra et al used a mouse model to show that the inhalation of Aspergillus caused EoE. They found that the allergen-challenged mice developed elevated levels of esophageal eosinophils and features of epithelial cell hyperplasia that mimic EoE. In addition, Fogg et al reported a case of a 21-year-old female with asthma and allergic rhinoconjunctivitis who also had EoE. The patient’s EoE became symptomatic with exacerbations during pollen seasons, followed by resolution during winter months.

Familial clustering of cases of EoE has led to the assumption that there may be a genetic predisposition to the disease. In recent years, several candidate genes have been identified as risk variants for the development of EoE. Among these are the genes that code for eotaxin-3, thymic stromal lymphoprotein (TSLP) and filaggrin. A genome-wide association approach to identify EoE risk variants was undertaken in two independent EoE and control populations, revealing a single susceptibility locus in both cohorts that corresponded to locus 5q22.1, in which 11 single nucleotide polymorphisms (SNPs) resided within a single haplotype block spanning the TSLP gene. TSLP has been implicated in the development of atopic disease previously, and more recently Noti et al showed that in a mouse model of eosinophilic esophagitis, neutralization with anti-TSLP antibody alleviated tissue eosinophilia associated with disease.

Clinical Manifestations

Eosinophilic esophagitis can occur in all age groups but traditionally presents in younger patients with a male to female ratio of about 3 : 1. However, with increased awareness of the disorder among internist-gastroenterologists, there has also been increased recognition of the disorder in adults. Estimates of prevalence are approximately 50 patients per 100,000 population, but EoE appears to be more prevalent in certain populations.

Patients typically present with one or more of the following symptoms: vomiting, regurgitation, nausea, epigastric or chest pain, water brash, globus and/or decreased appetite. Less common symptoms include growth failure and hematemesis. Esophageal dysmotility and dysphagia are less common in younger children but become increasingly prevalent in adolescents and adults. Symptoms can be frequent and severe in some patients but extremely intermittent and mild in others. The majority of patients may experience daily dysphagia or chronic nausea or regurgitation while others may have infrequent or rare episodes of dysphagia. Some patients develop coping mechanisms to adapt to their chronic dysphagia including over-chewing food, drinking excessively during meals to propel food downward, dipping foods in ‘lubricants’ such as ketchup or gravy and avoiding meats. It is important for the physician to perform a detailed history of these compensatory mechanisms. Up to 50% of patients manifest additional allergy-related symptoms such as asthma, eczema or rhinitis. Furthermore, more than 50% of patients have one or more parents with history of allergy ( Box 45-2 ).

Children with EoE have been studied in comparison to those with gastroesophageal reflux (GER). While the symptoms of vomiting and abdominal pain occurred similarly in both groups, dysphagia, diarrhea and growth failure were predominant in those with EoE ( Table 45-1 ).

Evaluation and Diagnosis

Patients with chronic refractory symptoms of gastroesophageal reflux disease (GERD) or dysphagia should undergo evaluation for EoE. While laboratory and radiologic assessment may be appropriate, the majority of these patients should undergo an upper endoscopy with biopsy. Historically, the diagnosis of EoE was often given when an isolated severe histologic esophagitis unresponsive to aggressive acid blockade, associated with symptoms similar to those seen in gastroesophageal reflux disease, was seen. The diagnosis is further supported if the patient responds both clinically and histologically to the elimination of a specific food. In the past, a 24-hour pH probe was required to demonstrate that the esophageal disease was not acid induced; however, more recent guidelines allow for diagnosis in the setting of appropriate clinical and histologic findings. According to the most recent consensus guidelines, the threshold of esophageal eosinophilia should be 15 or more eosinophils per HPF on esophageal biopsies.

However, very high levels of esophageal eosinophilia have been demonstrated with GER alone, emphasizing that failure of appropriate medical therapy is an important feature of the diagnosis. A more recently recognized condition, known as PPI-responsive esophageal eosinophilia (PPI-Ree), has also complicated the diagnostic picture. PPI-Ree was first discovered among cohorts of patients with symptoms and endoscopic and histologic findings characteristic of EoE, in whom all findings normalized after treatment with proton pump inhibitors. For these reasons, where possible, it is preferable to defer endoscopy until after a course of aggressive acid suppression with proton pump inhibitors. At that point, findings of esophageal eosinophilia are more likely to represent true EoE in the appropriate clinical setting. Currently, upper endoscopy with biopsy is the only diagnostic test that can accurately determine if the esophageal inflammation of EoE is present.

Once EoE is suspected, patients should be encouraged to seek an allergy consultation. Skin prick testing and serum allergen-specific IgE measurements may provide some clues to possible food allergens. Unfortunately, these tests are most useful in determining IgE-based allergic disorders. Since EoE is considered to be either a T cell mediated disease or a mixed IgE and T cell mediated disorder, the sensitivity and specificity of skin prick tests alone are low. Atopy patch testing (the placement of an antigen on the skin for several days followed by assessment for localized skin reaction) may be more useful in determining the antigens responsible for causing esophageal eosinophilia, although this remains to be established. If no specific antigen(s) are found through allergy testing, a trial of an elimination diet, consisting of removal of the antigens that most commonly cause EoE, can be attempted. The most common foods identified as causing EoE are milk, soy, egg and wheat. If all of these measures fail, an elemental diet utilizing an amino acid based formula should be considered. The assessment of success should be based on both the improvement of clinical symptoms and histologic improvement.

Once EoE has resolved, foods should be reintroduced in a systematic manner. Because of the possibility of delayed reactions, it is advisable to wait several days to one week between each new food introduction. This time period is usually sufficient to see a recurrence of symptoms; if symptoms develop, the food should be discontinued. However, in some cases symptoms do not occur despite recurrence of eosinophilic infiltration. A repeat endoscopy with biopsy is required in order to evaluate for the presence of esophageal mucosal injury. Since clinical symptoms often occur sporadically, biopsy remains the most important way to accurately determine the presence or resolution of EoE.

While upper endoscopy with biopsy can precisely determine the diagnosis, noninvasive diagnostic tests have proven to be less useful. These include the evaluation of serum IgE levels and quantitative peripheral eosinophils, radiographic upper gastrointestinal series (UGI), pH probe and manometry, allergen-specific IgE measurements and skin prick and patch testing. A promising new modality is the esophageal string test, where a string is swallowed but then anchored at the mouth so it can be removed and analyzed for the presence of eosinophil-derived proteins. Initial reports show that results from this test correlate strongly with histologic findings of eosinophilia.

EoE should be considered only when the eosinophilia is isolated strictly to the esophagus. To make an accurate diagnosis, the remainder of the gastrointestinal tract must be normal. When EoE is suspected, the sensitivity for detecting the disease is increased when more biopsies are obtained from the esophagus. Sensitivity seems to be highest when at least five biopsies are obtained.

EoE has been associated with visual findings on endoscopy: concentric ring formation called ‘trachealization’ or a ‘feline esophagus’, longitudinal linear furrows and patches of small, white papules on the esophageal surface. Most investigators believe that the esophageal rings and furrows are a response to full thickness esophageal tissue inflammation. The white papules appear to represent the formation of eosinophilic microabscesses ( Figures 45-1 and 45-2 ).

‘Trachealization’ or ‘felinization’ of the mid-esophagus in a patient with eosinophilic esophagitis. The terms arise from the ringed appearance of the esophagus that cause it to resemble a human trachea or a cat esophagus (which has rings of cartilage).

White plaques seen in the mid-esophagus in a patient with eosinophilic esophagitis.

In 2000, Fox et al utilized high-resolution probe endosonography in patients with EoE in order to determine the extent of tissue involvement. They compared eight patients identified with EoE to four control patients without esophagitis and discovered that the layers of the esophageal wall were thicker in EoE patients than in the control group (2.8 to 2.2 mm). Additionally, the mucosa to submucosa ratio (1.6 to 1.1 mm) and the muscularis propria thickness (1.3 to 1.0 mm) were greater in EoE patients. These findings suggested that EoE patients had more than just surface involvement of eosinophils.

Complications of Disease

While stomach pain, vomiting and failure to thrive are hallmarks of pediatric EoE, food impaction and dysphagia are often found in teenagers diagnosed with EoE. Food impaction prevalence is increasing in parallel with the incidence of EoE. This may be due to the fact that the esophagus in EoE is both more rigid and dysmotile than a normal esophagus. Up to 37% of patients with EoE have been shown to have abnormal esophageal peristalsis, either weak or absent. In addition, the distensibility of the esophagus in EoE patients with a history of food impaction and stricture is decreased.

In addition to food bolus impaction, esophageal stricture is another significant complication of EoE. Esophageal stricture not only causes esophageal dysfunction and dysphagia, but often requires esophageal dilation. There is enhanced collagen deposition in the lamina propria of patients with EoE when compared to patients with GERD. Excessive collagen deposition eventually leads to lumen narrowing and stricture. Stricture formation is part of the natural history of untreated EoE. Adults with longstanding untreated disease are more likely to develop esophageal stricture when compared to those with a relatively short duration of disease. Based on this finding, it is postulated that years of unremitting inflammation eventually lead to excessive esophageal collagen deposition and stricture.

While the pathogenesis of fibrosis in EoE is poorly understood, this complication can lead to decreased quality of life and lifelong dysphagia. Despite successful therapy, patients with EoE continue to have increased lamina propria collagen when compared to control patients. This suggests some degree of permanence in esophageal remodeling, underscoring the importance of prompt diagnosis.

Management

The identification and removal of allergic dietary antigens is the mainstay of treatment for EoE. While removal of the offending food(s) reverses the disease process in patients with EoE, in many cases the identification of these foods is difficult. Often, patients with EoE cannot correlate their gastrointestinal symptoms with the ingestion of specific foods. Several reports have demonstrated that several days may be required for symptoms to recur upon ingestion of antigens that cause EoE. Even when a particular food causing EoE has been eliminated, it may take days or weeks for the symptoms to resolve. In addition, although one food may be identified, there may be several other foods (not identified) that could also be contributing.

While attempts should be made to identify and eliminate potential food allergens through a careful history and the use of allergy testing, it may be difficult to determine the responsible allergenic foods; the administration of a strict diet, utilizing an amino acid based formula, is often necessary. The use of an elemental diet rapidly improves both clinical symptoms and histology in patients with EoE. Because of poor palatability, the elemental formula is commonly administered by continuous nasogastric feeding, although some more palatable options have emerged in the last few years. The diet may be supplemented with water, and some have also approved the use of a protein-free single antigen juice such as white grape or apple.

Reversal of symptoms typically occurs within 10 days with histologic improvement within 4 weeks. Although the strict use of an amino acid based formula may initially be difficult for patients (and parents) to accept, its benefits may outweigh the risks of other treatments and the rapid improvement in symptoms proves very reinforcing to families. While the use of other medications, such as corticosteroids, may temporarily improve the disease and its symptoms, the disease recurs upon their discontinuation. In contrast, when foods that cause EoE are identified through a combination of allergy testing, endoscopy, elimination and selective reintroduction, then lifelong remission without medication can be attained.

Treatment of true EoE with aggressive acid blockade, including medical and surgical therapy, has not been proven effective. Several published reports have demonstrated the failure of H ₂ blocker and proton pump therapy in patients with EoE. While acid blockade may improve clinical symptoms by improving acid reflux that occurs secondary to the underlying inflamed esophageal mucosa, it does not reverse the esophageal histologic abnormality. Although some case reports suggested that fundoplication was beneficial for patients with EoE, in 1997 Liacouras reported on two cases of failed Nissen fundoplication in patients who were diagnosed with severe eosinophilic esophagitis. Both patients underwent fundoplication for presumed acid reflux esophagitis unresponsive to medical therapy. However, post-surgical evaluation of both patients revealed ongoing clinical symptoms. Repeat esophagogastroduodenoscopy demonstrated persistent esophageal eosinophilia. Subsequently, both patients responded to oral corticosteroids with resolution of symptoms and histologic improvement.

Prior to 1997, reports suggested that systemic corticosteroids improved the symptoms of EoE in adults identified with a severe eosinophilic esophagitis. In 1997, Liacouras et al were the first to publish the use of oral corticosteroids in 20 children diagnosed with EoE. These patients were treated with oral methylprednisolone (average dose 1.5 mg/kg/day; maximum dose 48 mg/day) for 1 month. Symptoms were significantly improved in 19 of 20 patients by an average of 8 days. A repeat endoscopy with biopsy, 4 weeks after the initiation of therapy, demonstrated a significant reduction of esophageal eosinophils, from 34 to 1.5 eosinophils per HPF. However, upon discontinuation of corticosteroids, 90% had recurrence of symptoms.

In 1999, Faubion et al reported that swallowing a metered dose of aerosolized corticosteroids was also effective in treating the symptoms of EoE in children. Four patients diagnosed with EoE manifested by epigastric pain, dysphagia and a severe esophageal eosinophilia unresponsive to aggressive acid blockade were given fluticasone, 4 puffs twice a day. Patients were instructed to use an inhaler but to immediately swallow after inhalation in order to deliver the medication to the esophagus. Histologic improvement was not determined. Within 2 months, all 4 patients responded with an improvement in symptoms. Two patients required repeat use of inhalation therapy. Success with this therapy has been confirmed.

Later, Konikoff et al performed a randomized double-blind placebo-controlled trial utilizing swallowed fluticasone in patients with EoE. The study revealed symptom improvement and decreased esophageal eosinophils in those who received the study drug compared to those who received placebo. Aceves et al reported an effective alternative by using liquid budesonide mixed with a sucralose suspension.

Side-effects can include esophageal candidiasis and growth failure. As with all therapies that do not involve removal of antigens, symptoms often recur in patients upon discontinuation of the therapy.

Other forms of medical therapy that have been evaluated previously include the mast cell stabilizing agent cromolyn sodium and the leukotriene antagonist montelukast. While each of these medications represents an appealing option from a pathophysiologic standpoint, the available data do not support their use, based either upon lack of clinical improvement or minimal to no histologic resolution.

The latest innovation in therapy is the use of biologic agents directed at the cytokine interleukin 5 (IL-5). IL-5 plays in important role in eosinophil recruitment, activation and proliferation. In the past, two small studies demonstrated the effectiveness of anti IL-5 in improving both symptoms and esophageal histology. The first large-scale pediatric trial utilizing an anti-IL-5 monoclonal antibody, reslizumab, had mixed results. Patients receiving active drug showed improvement in biopsy findings compared to placebo. However, subjects receiving both active drug and placebo showed symptomatic improvement, which resulted in failure to meet one of the study endpoints required to receive FDA approval. The drug is still in testing for the indication of eosinophilic asthma.

Etiology

EoG affects patients of all ages, with a slight male predominance. Most commonly, eosinophils infiltrate only the mucosa, leading to symptoms associated with malabsorption such as growth failure, weight loss, diarrhea and hypoalbuminemia. Mucosal EoG may affect any portion of the gastrointestinal tract. A review of the biopsy findings in 38 children with EoG revealed that all patients examined had mucosal eosinophilia of the gastric antrum. Seventy-nine percent of the patients also demonstrated eosinophilia of the proximal small intestine, with 60% having esophageal involvement and 52% having involvement of the gastric corpus. Those with colonic involvement tended to be less than 6 months of age and were ultimately classified as having allergic colitis.

Details of the etiology of EoG remain unknown, although it is now recognized to be a result of both IgE and non-IgE mediated sensitivity. The association between IgE mediated inflammatory response (typical allergy) and EoG is supported by the increased likelihood of other allergic disorders such as atopic disease, food allergies and seasonal allergies. Specific foods have been implicated in the cause of EoG in some patients. In contrast, the role of non-IgE mediated immune dysfunction, in particular the interplay between lymphocyte-produced cytokines and eosinophils, has received attention. IL-5 is a chemoattractant responsible for tissue eosinophilia. Desreumaux et al found that among patients with EoG, the levels of IL-3, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) were significantly increased as compared to control patients. Once recruited to the tissue, eosinophils may further recruit similar cells through their own production of IL-3 and IL-5, as well as production of leukotrienes. This mixed type of immune dysregulation in EoG has implications for the way this disorder is diagnosed, as well as the way it is treated.

Clinical Manifestations

The most common symptoms of EoG include colicky abdominal pain, bloating, diarrhea, weight loss, dysphagia and vomiting. In addition, up to 50% of patients have a past or family history of atopy. Features of severe disease include gastrointestinal bleeding, iron deficiency anemia, protein losing enteropathy (hypoalbuminemia) and growth failure. Approximately 75% of affected patients have an elevated blood eosinophilia. Males are more commonly affected than females. Rarely, ascites can occur.

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. 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, then EoG should be considered in the diagnosis before surgical intervention.

Uncommon presentations of EoG include acute abdomen (even mimicking acute appendicitis) or colonic obstruction. There have also been reports of serosal infiltration with eosinophils, with associated complaints of abdominal distention, eosinophilic ascites and bowel perforation.

Evaluation and Diagnosis

EoG should be considered in any patient with a history of chronic symptoms including vomiting, abdominal pain, diarrhea, anemia, hypoalbuminemia or poor weight gain in combination with the presence of eosinophils in the gastrointestinal tract. Other causes of eosinophilic infiltration of the gastrointestinal tract include the other disorders of the eosinophilic gastroenteropathy spectrum, as well as parasitic infection, inflammatory bowel disease, neoplasm, chronic granulomatous disease, collagen vascular disease and the hypereosinophilic syndrome.

A number of tests may aid in the diagnosis of EoG, however no single test is pathognomonic and there are no standards for diagnosis. Eosinophils in the gastrointestinal tract must be documented before EoG can be truly entertained as a diagnosis. This is most readily done with biopsies of either the upper gastrointestinal tract through esophagogastroduodenoscopy or the lower tract through flexible sigmoidoscopy or colonoscopy. A history of atopy supports the diagnosis but is not a necessary feature. Peripheral eosinophilia or an elevated IgE level occurs in approximately 70% of affected individuals. Measures of absorptive activity such as the D-xylose absorption test and lactose hydrogen breath testing may reveal evidence of malabsorption, reflecting small intestinal damage. Radiographic contrast studies may demonstrate mucosal irregularities or edema, wall thickening, ulceration or luminal narrowing. A lacy mucosal pattern of the gastric antrum known as areae gastricae is a unique finding that may be present in patients with EoG.

Evaluation of other causes of eosinophilia should be undertaken, including stool analysis for ova and parasites and serologic tests for specific parasites in endemic areas. Signs of intestinal obstruction warrant abdominal imaging. Allergen-specific IgE testing, as well as skin testing for environmental antigens, is rarely useful. Skin testing using both traditional prick tests and patch tests may increase the sensitivity for identifying foods responsible for EoG by evaluating both IgE mediated and T cell mediated sensitivities.

Management

There is as much ambiguity in the treatment of EoG as there is in its diagnosis. This is in large part because the entity of EoG was defined mainly by case series, each of which employed its own mode of treatment. Since EoG is such a difficult disease to diagnose and relatively rare in prevalence, randomized trials for its treatment are uncommon, leading to considerable debate as to the optimal treatment.

Food allergy is considered one of the potential underlying causes of EoG. The elimination of pathogenic foods, as identified by any form of allergy testing or by random removal of the most likely antigens, should be a first-line consideration. Unfortunately, this approach results in improvement in a limited number of patients. In severe cases, or when other treatment options have failed, the administration of a strict diet, utilizing an elemental formula, has been shown to be successful. In these cases, elemental formula provided as the sole source of nutrition has been reported to be effective in the resolution of clinical symptoms and tissue eosinophilia.

When the use of a restricted or elemental diet fails, corticosteroids are often employed due to their high likelihood of success in attaining remission. However, when weaned, the duration of remission is variable and can be short-lived, leading to the need for repeated courses or continuous low doses of steroids. In addition, the chronic use of corticosteroids carries an increased likelihood of undesirable side-effects, including cosmetic problems (cushingoid facies, hirsutism, acne), decreased bone density, impaired growth and personality changes. A response to these side-effects has been to look for substitutes that may act as steroid-sparing agents, while still allowing for control of symptoms. Anecdotally, immunomodulators more commonly used as steroid-sparing agents in inflammatory bowel disease, such as mercaptopurine or azathioprine, have been used with some success.

Orally administered cromolyn sodium also has been effective in some patients, and recent reports have detailed the efficacy of other oral antiinflammatory medications. Montelukast, a selective leukotriene receptor antagonist used to treat asthma, has been reported to successfully treat two patients with EoG. Treatment of EoG with inhibition of leukotriene D4, a potent chemotactic factor for eosinophils, relies on the theory that the inflammatory response in EoG is perpetuated by the presence of the eosinophils already present in the mucosa. This therapy causes an interruption in the chemotactic cascade and breaks the inflammatory cycle. Suplatast tosilate, another suppressor of cytokine production, has also been reported as a treatment for EoG.

Given the possibilities for treatment of EoG, the combination of therapies incorporating the best chance of success with the smallest likelihood of side-effects should be employed. When particular food antigens that may be causing disease can be identified, elimination of those antigens should be first-line therapy. When testing fails to identify potentially pathogenic foods, systematic elimination of the most commonly involved foods can be employed. If this approach fails, a total elimination diet with an amino acid based formula should be considered. Trials of nonsteroidal antiinflammatory medications such as cromolyn, montelukast and suplatast are a reasonable option, although some might prefer to wait for more detailed studies. Monoclonal antibodies against IL-5 may also hold some promise in the future, although current studies are limited to patients with EoE; further research will be necessary in the EoG population.

When other treatments fail, corticosteroids remain a reliable treatment for EoG, with attempts at limiting the total dose or the number of treatment courses where possible. Due to the diffuse and inconsistent nature of symptoms in this disease, serial endoscopy with biopsy is a useful and important modality for monitoring disease progression.

Etiology

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 nonantigenic proteins. 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. As a result, ingested antigens may have an increased propensity for being presented intact to the immune system. These intact antigens have the potential to stimulate the immune system and drive an inappropriate response directed at the gastrointestinal tract. Because the major component of the young infant’s diet is milk or formula, it stands to reason that the inciting antigens in EoP are derived from the proteins found in them. Cow’s milk and soy proteins are the foods most frequently implicated in EoP.

Commercially available infant formulas most commonly utilize cow’s milk as the protein source. There are at least 25 known immunogenic proteins within cow’s milk, beta-lactoglobulin and the caseins being the most antigenic. It is thought that up to 7.5% of the population in developed countries exhibit cow’s milk allergy, although there is wide variation in the reported data. Soy protein allergy is considered to be less common than cow’s milk allergy, with a reported prevalence of approximately 0.5%. However, soy protein intolerance becomes more prominent in individuals who have developed milk protein allergy, with prevalence from 15% to 50% or more in milk protein sensitized individuals. For this reason, substitution of a soy protein based formula for a milk protein based formula in patients with suspected milk protein proctocolitis is often unsuccessful.

Maternal breast milk represents a different challenge to the immune system. Up to 50% of cases of EoP occur in breastfed infants; however it is thought that, rather than developing an allergy to human milk protein, the infants are manifesting allergy to antigens ingested by the mother and transferred via the breast milk. The transfer of maternal dietary protein via breast milk was first demonstrated in 1921. More recently, the presence of cow’s milk antigens in breast milk has been established.

When a problem with antigen handling occurs, whether secondary to increased absorption through an immature gastrointestinal tract or through a damaged epithelium secondary to gastroenteritis, sensitization of the immune system results. Once sensitized, the inflammatory response is perpetuated with continued exposure to the inciting antigen. This may explain the reported relationship between early exposure to cow’s milk protein or viral gastroenteritis and the development of allergy.

Clinical Manifestations

Diarrhea, rectal bleeding and increased mucus production are the typical symptoms seen in patients who present with EoP. There is a bimodal age distribution with the majority of patients presenting in infancy (mean age at diagnosis of 60 days ) and the other group presenting in adolescence and early adulthood.

The typical infant with EoP 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 assumption 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 are generally well appearing and rarely appear ill. Other manifestations of gastrointestinal tract inflammation such as vomiting, abdominal distention or weight loss almost never occur and would be suggestive of another problem such as food protein induced enterocolitis syndrome (FPIES) ( Table 45-2 ).

TABLE 45-2

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