IgE-Mediated Allergy and Anaphylaxis

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. 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.

Blinded food challenges have shown that symptoms referable to the gastrointestinal tract in IgE-mediated allergy typically begin within minutes of ingestion, although occasionally they may be delayed for up to 2 hours. Symptoms tend to be short-lived, lasting 1 to 2 hours and include nausea, vomiting, abdominal pain, and diarrhea; they may also include oral symptoms, skin manifestations, wheezing, or airway edema.

Anaphylactic reactions to food ingestion are life threatening. For the purpose of this discussion, the term anaphylaxis is limited to those IgE-mediated reactions that cause upper airway obstruction, hypotension, and circulatory collapse. Although any protein may be implicated, certain foods have a propensity to cause severe reactions in susceptible persons: cow’s milk, egg, peanut, and shellfish. The altering of food protein antigens through cooking or prior hydrolysis does not preclude a type I allergic reaction because some proteins are relatively resistant to denaturation.

Meanwhile, the oral allergy syndrome (OAS) is another IgE-mediated allergy, where the reaction is typically oral itching or tingling. Occasionally, facial or throat swelling may occur as well; it is unclear whether OAS causes other gastrointestinal symptoms such as pain or diarrhea. 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.

Patients with a history of a significant reaction to one or more foods should be tested by skin prick against those foods and against a limited battery of common food allergens (milk, soy, egg, peanut, fish, and wheat). Skin testing has a sensitivity of 90% to 100% depending on the antigen, so patients with negative skin testing are unlikely to have IgE-mediated disease and should be challenged openly with the food in question. Non–IgE-mediated hypersensitivity may still cause symptoms on challenge, but these may be delayed for hours or days. IgE-RAST testing for specific foods does not have greater positive or negative predictive value than skin prick testing, and combining the two does not improve the diagnostic yield. The specificity of skin prick testing for food allergies ranges from 40% to 80%, which implies that the possibility of a false-positive skin test is not inconsequential. Therefore, the use of skin testing in the evaluation of food allergy should be limited to cases where there is a high clinical suspicion for allergies as the etiology of symptoms, which increases the positive predictive value of the test.

If IgE-RAST or skin prick tests are positive, the food should be avoided for at least 3 weeks; if symptoms improve, the elimination diet should be continued. If there is no improvement, then open or single-blind challenges with the food can be given to try to elicit a response. These challenges should be performed in a setting in which access to emergency treatment of allergic reactions is available; this is generally best handled by an allergist.

Positive challenges should lead to consultation with a dietitian to educate the patient and family concerning avoidance of the food and to ensure that adequate nutrition is maintained. Groups such as The Food Allergy and Anaphylaxis Network and the American Partnership for Eosinophilic Disorders provide support and educational materials for families. Patients with a history of serious reactions to foods should be provided with an epinephrine kit for home use, proper instruction on how the device is used, and a MedicAlert bracelet.

Food Protein–Induced Enterocolitis Syndrome

The food protein–induced enterocolitis syndrome, often abbreviated as FPIES, is a non–IgE-mediated gut reaction to ingested food(s). FPIES is most commonly characterized by a severe reaction that includes profuse vomiting and diarrhea, with an onset between 1 and 6 hours after ingestion of an inciting food. The most common food antigens to cause FPIES are milk and soy, although the reaction has been seen with numerous foods. Rice may be the most common solid food, although once one is sensitized to one grain, it is common to react to various grains.

FPIES occurs most frequently in infancy, but somewhat later than the onset of typical milk-protein intolerance. The reaction with FPIES can be severe, often confused with an episode of gastroenteritis. Dehydration is the most common serious consequence of an FPIES reaction, and the patient may present with significant lethargy or shock, as well as bloody stool, anemia, and hypoalbuminemia. In addition, transient methemoglobinemia has been reported as a result of an FPIES reaction. It may take several episodes before the trigger of the episodes is uncovered, or symptoms may become chronic if the inciting food is a common component of the diet. It can be difficult to isolate the exact food(s) responsible for the reaction.

Because FPIES is not IgE mediated, traditional allergy testing (i.e., skin prick or RAST) is not useful for identifying the trigger foods. Atopy patch testing (APT) has been used successfully to predict foods that cause FPIES, confirmed by oral food challenge.

Etiology

EoE is caused by an abnormal immunologic response to specific antigens. In most cases the antigens responsible are food antigens, although there appears to be a contribution from other environmental antigens in certain individuals. Although several studies have documented resolution of EoE with the strict avoidance of food antigens, in 1995, Kelly 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, with 10 patients adhering 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 eight patients and improvement in two). In addition, all 10 patients demonstrated a significant improvement in esophageal eosinophilia. All patients reverted to previous symptoms upon reintroduction of foods.

Although an exact explanation for this type of response was not determined, Kelly suggested an immunologic basis as the cause for EoE, secondary to a delayed hypersensitivity or a cell-mediated hypersensitivity response. More recently, Spergel 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 APT, he 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 eosinophilic esophagitis 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 as patients improved with 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. In addition, in patients with EoE, symptoms do not always occur immediately after reintroduction of the foods. It may take several days for symptoms to develop, suggesting a mixed IgE and T-cell–mediated allergic response, or strictly a T-cell–delayed mechanism in the pathogenesis of this disease. Although 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 and Rothenberg 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, Spergel reported a case of a 21-year-old woman 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 those 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. Of interest, TSLP has been implicated previously in the development of atopic disease.

However, genetic factors alone do not account for the development of EoE. As mentioned previously, environmental exposure to allergens in the diet, and possibly aeroallergens, are a necessary factor for developing disease. It remains unclear why genetically susceptible individuals develop EoE in the presence of certain allergens. Atopic diseases such as asthma seem to be on the rise, and it is possible that EoE is just another manifestation of this phenomenon. Recent evidence suggests that early exposures may also influence risk of developing EoE. In a small cohort study, Jensen found that antibiotic exposure in infancy conferred a 6-fold increased risk of developing EoE in childhood, whereas other factors such as cesarean section, preterm birth, and formula exposure also had trends toward increased risk.

Clinical Manifestations

Eosinophilic esophagitis can occur in all ages 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 the disease appears to be more prevalent in certain populations. Based on insurance claims, men 35 to 39 years of age in the United States have a prevalence of greater than 100 per 100,000. Among patients with airway complaints such as cough referred to an aerodigestive referral center staffed by otolaryngologists, 3.6% were found to have EoE.

Patients typically present with one or more of the following symptoms: vomiting, regurgitation, nausea, epigastric or chest pain, water brash, globus, and 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 while extremely intermittent and mild in others. The majority of patients may experience daily dysphagia or chronic nausea or regurgitation, whereas others may have infrequent or rare episodes of dysphagia. 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 37-2 ).

Children with EoE have been studied in comparison to those with gastroesophageal reflux. Although the symptoms of vomiting and abdominal pain occurred similarly in both groups, in children with EoE, dysphagia, diarrhea, and growth failure are predominant. In addition, patients with EoE are more likely to have had allergic symptoms, another family member with an allergic history, and peripheral eosinophilia. Patients with EoE have higher numbers of eosinophils in their esophagus and also tend to have relatively normal pH-metry when compared to those with GER ( Box 37-3 ).

Evaluation and Diagnosis

Patients with chronic refractory symptoms of gastroesophageal reflux disease or dysphagia should undergo evaluation for EoE. Although 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 was seen associated with symptoms similar to those seen in gastroesophageal reflux disease. The diagnosis is further supported if the patient responds both clinically and histologically to the elimination of a specific food or foods. In the past, a 24-hour pH probe was required to demonstrate that the esophageal disease was not acid induced; however, guidelines that are more recent 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 high power field (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 proton-pump inhibitor (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 PPIs. In a prospective study of 173 adults undergoing upper endoscopy for dysphagia, 66 patients were found to have more than 15 eosinophils per HPF on biopsy. Of these 173 adults, 40 had persistent eosinophilia and 24 had improvement consistent with PPI-Ree. Yet, it also is possible that those with PPI-Ree eventually revert to an EoE phenotype, as demonstrated in four pediatric patients with PPI-Ree who remained on PPI yet had recurrence of eosinophilia in the esophagus. For these reasons, where possible, it is preferable to defer endoscopy until after a course of aggressive acid suppression with PPIs. 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. The most common foods identified as causing EoE are milk, soy, egg, wheat, nuts, fish, and shellfish. Skin prick testing and serum RAST tests may provide some clues to possible food allergens. Unfortunately, these tests are most useful in determining IgE-based allergic disorders. Because EoE is considered 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. APT (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 and should be utilized if available. 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. 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 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 to evaluate for the presence of esophageal mucosal injury. Because clinical symptoms often occur sporadically, biopsy remains the most important way to accurately determine the presence or resolution of EoE.

Although upper endoscopy with biopsy can precisely determine the diagnosis, noninvasive diagnostic tests have proven to be less useful, yet remain an area of focus. These include the evaluation of serum IgE levels and quantitative peripheral eosinophils, radiographic upper gastrointestinal series (UGI), pH probe and manometry, RAST testing, and skin prick and patch testing. When used alone, serum IgE levels and serum eosinophils have been found to be unreliable, as these tests usually respond to environmental allergens as well as ingested or inhaled allergens. Although radiographs determine anatomic abnormalities, these tests cannot identify tissue eosinophilia. Patients with EoE usually have normal or borderline pH-metry. These patients may have mild gastroesophageal reflux disease (GERD) secondary to abnormalities in esophageal motility due to tissue eosinophilic infiltration. 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 esophageal mucosa. In the past, early reports suggested that eosinophilia in EoE was more characteristic in the mid-esophagus than the distal esophagus (which is more likely to have eosinophils relating to acid reflux); however, it has now been demonstrated that a severe mucosal eosinophilia can occur in either the distal or proximal 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,” and 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 micro-abscesses ( Figures 37-1 and 37-2 ).

“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 1999, Ruchelli evaluated 102 patients presenting with GERD symptoms who also were found to have at least one esophageal eosinophil without any other gastrointestinal abnormalities. Patients were subsequently treated with aggressive acid blockade. It was demonstrated that the treatment response could be classified into three categories. Patients who improved had on average 1.1 eosinophils per HPF, patients who relapsed upon completion of therapy had 6.4 eosinophils per HPF, and patients who remained symptomatic had on average 24.5 eosinophils per HPF.

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

Management

The identification and removal of allergic dietary antigens are the mainstay of treatment for EoE. Although removal of the offending food(s) reverses the disease process in patients with EoE, in many cases the isolation of these foods is difficult. Because of the delayed hypersensitivity response, often patients with EoE cannot correlate their gastrointestinal symptoms with the ingestion of a specific food. Some reports have demonstrated several days for symptoms to recur upon ingestion of antigens that cause EoE. Even when a particular food causing EoE has been isolated, 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.

Although 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 allergic foods; the administration of a strict diet utilizing an amino acid–based formula is often necessary to do so. As established previously, 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 there are some more palatable options that have emerged in the last few years. The diet may be supplemented with water, and some have approved the use of a protein-free single-antigen juice such as white grape or apple. Many patients also tolerate foods made solely of highly refined carbohydrates such as certain lollipops; however, it is usually better to introduce these other foods somewhat later in the elemental diet.

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 reinforcing to families. The use of other medications, such as corticosteroids, may temporarily improve the disease and its symptoms; however, 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, a lifelong remission without medication can be attained.

Treatment of true EoE with aggressive acid blockade, including medical and surgical therapy, has not proven effective. Several published reports have demonstrated the failure of H2 blocker and PPI therapy in patients with EoE. Acid blockade may improve clinical symptoms by improving acid reflux that occurs secondary to the underlying inflamed esophageal mucosa; however, it does not reverse the esophageal histologic abnormality. Although some case reports have 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 that was unresponsive to medical therapy, but postsurgical evaluation of both patients revealed ongoing clinical symptoms. Repeat Esophagogastroduodenoscopy (EGD) 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 was 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, on discontinuation of corticosteroids, 90% had recurrence of symptoms.

In 1999, Faubion 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, four puffs twice a day. Patients were instructed to use an inhaler but to swallow immediately after inhalation to deliver the medication to the esophagus. Histologic improvement was not determined. Within 2 months, all four patients responded with an improvement in symptoms. Two patients required repeat use of inha­lation therapy. Success with this therapy has been confirmed.

Later, Konikoff 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 study drug compared to those who received placebo. In addition to swallowed fluticasone, Aceves 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 on 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. Although each of these medications represent appealing options from a pathophysiologic standpoint, the available data do not support their use, based either on lack of clinical improvement or minimal to no histologic resolution.

The latest innovation in therapy includes the use of biologic agents directed at the cytokine interleukin 5 (IL-5), which 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 in meeting one of the study endpoints required to receive U.S. Food and Drug Administration (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 younger than 6 months of age and were ultimately classified as having allergic colitis.

The exact etiology of EoG remains unknown, although it is now recognized as a result of both IgE-mediated 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 as 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 also 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 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 in 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. Other 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 infants, 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, EoG should be considered, if possible, 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 distension, 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. RAST testing and skin testing for environmental antigens are 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 their own mode of treatment. Because EoG is a difficult disease to diagnose and relatively rare, randomized trials for its treatment are uncommon, leading to considerable debate as to which treatment is best.

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 for 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 the patient is weaned from the corticosteroids, 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, and 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 anti-inflammatory 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 causing an interruption in the chemotactic cascade breaking the inflammatory cycle. Suplatast tosilate, another suppressor of cytokine production has also been reported as a treatment for EoG.

Given the options 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 employed as a first-line therapy. When testing fails to identify potentially pathogenic foods, a systematic elimination of the most commonly involved foods can be employed. If this approach fails, total elimination diet with an amino acid–based formula should be considered. Trials of nonsteroidal anti-inflammatory 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 those 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 use of 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.