Eosinophilic Esophagitis: A Subset of Eosinophilic Gastroenteritis

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1 Eosinophilic Esophagitis: A Subset of Eosinophilic Gastroenteritis Chris A. Liacouras, MD and Jonathan E. Markowitz, MD Address University of Pennsylvania School of Medicine, The Children s Hospital of Philadelphia, 324 South 34th Street, Philadelphia, PA 19104, USA. Current Gastroenterology Reports 1999, 1: Current Science Inc. ISSN Copyright 1999 by Current Science Inc. Eosinophilic gastroenteritis (EG) was first described over 50 years ago. Despite its long history, it remains an ill-defined and poorly understood entity. EG can present in a number of ways, none of which are exclusive to the disorder. EG has features of allergy and immune dysregulation but does not clearly fit into the category of allergic or immune disorder. While EG has been reported to affect all locations and layers of the gastrointestinal tract, the vast majority of reported cases have demonstrated mucosal involvement of the gastric antrum and small intestine in addition to disease activity of other locations of the gastrointestinal tract. Recently, several reports have identified a disease consisting of an isolated esophageal eosinophilia. Eosinophilic esophagitis (EE), also known as primary eosinophilic esophagitis or idiopathic eosinophilic esophagitis, occurs in adults and in children and represents a subset of EG with an isolated severe esophageal eosinophilia. Patients with EE present with symptoms similar to those of gastroesophageal reflux but are unresponsive to antireflux medication. Reports have demonstrated that patients with EE respond to either dietary restriction or corticosteroids. Introduction This article reviews the history, presentation, diagnosis, and treatment of eosinophilic gastroenteritis (EG) and eosinophilic esophagitis (EE) as well as speculation on the association between EG and EE. In addition, a summary of the recent literature regarding EE and a comparison of patients presenting with symptoms and histologic features of gastroesophageal reflux are presented. Eosinophilic Gastroenteritis Pathophysiology The role of the eosinophil in eosinophilic gastritis is unclear, but its presence is the unifying factor in the diagnosis. Eosinophilic granules serve in the killing of parasites and act as inflammatory mediators and chemotactic agents [1]. Tissue damage may result from the interplay between immunoglobulins, complement, eosinophils, and other inflammatory cells. Antibody antigen complexes may be responsible for the attraction of eosinophils into the tissue of the gastrointestinal tract in association with complement activation and deposition [2]. Mast-cell associated mediators have also been shown to affect eosinophils and may play a role in the mediation of disease in EG. Once present in the tissue, the eosinophil may possess the ability to modulate disease in positive or negative ways. The cell may serve to control the inflammatory cascade from mast cell degranulation. Enzymes present in eosinophil granules contain enzymes that counteract the damaging substances present in mast cells. However, eosinophil granules also contain vasoactive substances such as platelet activating factor and leukotrienes, which may contribute to the inflammatory and clinical features of the disease [3]. The relationship between eosinophils and mast cells increases the confusion in categorizing EG. Mast cells typically are thought of in allergic disease, but IgE levels in EG are not consistently elevated. Almost 30 years ago, Klein et al. classified EG into three categories: mucosal, muscular, and subserosal. Mucosal EG is the most common form and is signified by mucosal infiltration of eosinophils on biopsy or gastrointestinal edema on radiographic study [4]. Muscular EG is defined by eosinophilic infiltration of the muscular layer of the intestine and is associated with stenosis or obstruction of the gastrointestinal tract without ascites. Serosal EG is the least common form of EG and represents eosinophilic infiltration of the serosal layer associated with eosinophilic ascites. The diagnosis of EG is often missed. Biopsy results do not always coincide with the clinical picture, perhaps because of the patchy nature of the disease or the possibility of not identifying an eosinophilia with random intestinal biopsy. Presentation Eosinophilic gastroenteritis affects male and female patients of all ages [5]. The presenting features of EG are nonspecific. Vomiting and abdominal pain are the most common symptoms and can occur in all presentations regardless of the

2 254 Pediatric Gastroentrology layer of infiltration [6 ]. Other common symptoms corresponding to mucosal disease include growth failure, anemia (occult blood loss), weight loss, and diarrhea [7]. Acute colitis with grossly bloody stools is a common presentation in infants but rarely occurs in children aged over 2 years [8]. Mucosal EG has been reported to affect any portion of the gastrointestinal tract. In the majority of cases, the gastric antrum and small bowel are affected, resulting in nausea, vomiting, and epigastric pain. Patients with muscular EG present with symptoms of gastrointestinal obstruction or dysmotility. The muscular layer of the gastric antrum is most commonly affected and typically causes vomiting, abdominal pain, and delayed gastric emptying. Involvement of the small intestine and colon is less likely. Patients with serosal EG present with symptoms from ascites or intestinal perforation. Extraintestinal infiltration has also been described. In contrast to other forms of EG, eosinophilic colitis or proctitis commonly represents sensitivity to cow s milk or soy protein, and symptoms abate with elimination of the offending antigen. Infants affected by this type of EG commonly lack systemic symptoms, leading to speculation that this disease may be a separate entity. Evaluation Eosinophilic gastroenteritis should be considered in any patient with a history of chronic vomiting, abdominal pain, diarrhea, anemia, hypoalbuminemia, or poor weight gain. Other associated findings include a peripheral eosinophilia or a history of allergies, eczema, asthma, or chronic rhinitis. A history of atopy is present in 50% of patients. Laboratory evaluation including serum total eosinophil and IgE levels may be elevated. D-xylose absorption or disaccharidase activity may be decreased, reflecting intestinal mucosal damage. Radiographic evaluation may demonstrate gastrointestinal involvement by showing mucosal irregularities or edema, wall-thickening, polyps, ulceration, and lumenal narrowing. The lacy, antral mucosal pattern known as areae gastricae is a more unique finding seen in EG. While the majority of these findings are nonspecific, barium studies may provide information on the location of disease. Demonstration on biopsy of eosinophilic infiltration of various portions of the gastrointestinal tract continues to be the mainstay of diagnosis of EG. In 1986, Goldman and Proujansky [8] reviewed 53 cases of allergic proctitis and gastroenteritis in children. Thirty-eight patients were identified as having symptoms and biopsy findings consistent with EG. Of the 38 patients with EG, all were found to have a mucosal eosinophilia of the gastric antrum. Seventy-nine percent also demonstrated a mucosal eosinophilia of the small intestine (duodenum), 60% had esophageal involvement, and in 52% eosinophilia was found in the gastric corpus. The majority of these patients had upper and lower gastrointestinal symptoms with multiple relapses, and many required corticosteroid therapy. In contrast, the remaining 15 patients were diagnosed with allergic proctitis. The majority of these children were aged less than 6 months and responded to dietary change without relapse. While the gastric antrum appears to be the most common location of disease, the patchy nature of the disease and the lack of full-thickness specimens on most endoscopic biopsies can lead to false negative biopsy results. Treatment Because of the heterogeneous nature of eosinophilic esophagitis, treatment choices vary. In some cases of EG, a clear inciting food can be determined. Allergy testing (skin and blood) may be performed, but often no specific antigen is found. In cases of known food antigen sensitivity, removal of the antigen is generally sufficient to induce remission. In cases where a specific food cannot be blamed for the symptoms, other treatments must be incorporated. Mast cell stabilizers such as oral cromolyn preparations have provided minimal success [8]. The use of elemental diets (amino acid formula preparations) has provided some success; however, patient compliance is usually very difficult. Upon introduction of an elemental diet, all other foods must be discontinued. The diet is continued for at least 3 weeks while symptoms are monitored. The reintroduction of foods occurs by adding one new food to the diet every 3 to 4 days. This slow reintroduction of foods is essential because many of the symptoms seem not to be caused by an immediate IgEhypersensitivity reaction but instead evolve later, consistent with a cell-mediated response. Thus, standard food hypersensitivity challenge testing often demonstrates no reaction, but symptoms may still occur several days after antigenic administration. Systemic corticosteroids have been the gold standard for inducing remission; however, the disease commonly relapses upon steroid withdrawal, necessitating repeated courses of steroids. While steroids provide effective treatment, long-term steroid use has been linked to serious side effects including bone demineralization, growth failure, obesity, diabetes, psychosis, and behavioral disorders. Eosinophilic Esophagitis History During the last 25 years, several studies have identified patients with a severe eosinophilic esophagitis suggesting an etiology other than acid reflux. In 1977 one of the first cases of esophageal eosinophilia was reported by Dobbins [9], involving a case of a 51-year-old male patient with asthma and allergies who developed dysphagia and substernal chest pain. Esophageal biopsies revealed a focal, marked eosinophilic infiltrate. Small bowel biopsies demonstrated villous flattening and an eosinophilia. The patient was diagnosed with eosinophilic gastroenteritis. In 1978, Landres [10] reported on the case of a patient with achalasia associated

3 Eosinophilic Esophagitis: A Subset of Eosinophilic Gastroenteritis Liacouras and Markowitz 255 with esophageal eosinophilia who underwent esophageal myotomy that revealed eosinophilic infiltration of the muscular layer. In 1983, Matzinger [11] described an adolescent with dysphagia, food allergy, and a peripheral eosinophilia who underwent esophageal biopsy, which revealed eosinophilic infiltration of both the esophagus and stomach. In 1985, Lee [12] reported on a series of 11 patients with a severe esophageal eosinophilia of more than 10 esophageal eosinophils per high power field (HPF) who presented with dysphagia, heartburn, vomiting, and esophageal strictures (three of 11). While this author suggests that reflux occurred in the majority, reflux was not documented by 24-hour ph probe. One patient was given steroids and clinically improved. Between 1978 and 1990, several reports were published linking radiographic abnormalities with esophageal eosinophilia [13 15]. Clinically, patients described in these reports presented with dysphagia, heartburn, chest pain, peripheral eosinophilia, regurgitation, and vomiting. In the majority of these patients, barium radiographic studies demonstrated an esophageal stricture. While most of these patients underwent repeated esophageal dilatation, one patient was given corticosteroids and subsequently both the clinical symptoms and the esophageal stricture resolved. In 1993, Attwood [16] reported on one of the first studies comparing patients with isolated esophageal eosinophilia to patients with gastroesophageal reflux. The author described 12 patients presenting with dysphagia who had more than 20 esophageal eosinophils/hpf (mean 56 eosinphils/hpf). All had visually normal esophageal mucosa and no esophageal anatomic abnormality, 11 had normal ph monitoring, and seven had evidence of an allergic disorder. Only one patient had antral eosinophilia. This group was compared to another group, consisting of 90 patients with medically responsive gastroesophageal reflux (documented by 24-hour ph probe); only 43 of these patients had esophageal eosinophils and to a much lesser degree (mean 3.3 eosinphils/ HPF). The author suggested that these patients represent a new clinicopathologic syndrome not previously described. Similarly, in 1995, Vitellas [4] reported on 13 male patients with idiopathic eosinophilic esophagitis and showed that the majority of these patients responded to corticosteroids. The patients clinical symptoms included dysphagia (12 of 13), allergic manifestations (10 of 13), peripheral eosinophilia (12 of 13) and proximal esophageal strictures (10 of 13). Vitellas suggests that the identification of these patients is important because treatment with corticosteroids is much more effective than esophageal dilatation. Pathology Since 1970, the histologic hallmarks for reflux esophagitis have been basal zone hyperplasia, elongated papillae, and intraepithelial neutrophils [17 20]. Other nonspecific findings include dilated vascular channels in the lamina propria papillae and distended squamous or balloon cells. In 1982, Winter [21] reported the presence of intraepithelial eosinophils as an added criterion for the diagnosis of reflux esophagitis in children. In this study of 46 symptomatic pediatric patients and nine control subjects, the presence of esophageal eosinophils was correlated with 24-hour ph probe monitoring, esophageal manometry, and other histologic features of gastroesophageal reflux, including papillary length and basal zone thickness. The presence of one or more intraepithelial eosinophils in the esophagus was established as a specific indicator of esophagitis. Abnormal esophageal acid clearance was correlated with other accepted morphologic features of esophageal injury. In addition, it was suggested that eosinophils were diagnostic of reflux esophagitis even if other accepted histologic abnormalities were absent. Although the majority of eosinophils were observed in the distal esophagus, the presence of more proximal eosinophils was associated with increasingly abnormal ph probe results. These findings were later confirmed in adults [22]. Apart from the diagnosis of reflux esophagitis, large numbers of esophageal eosinophils have been identified in children with eosinophilic gastroenteritis or allergic gastroenteritis [8]; however, in all of these patients, eosinophils were also present in the gastric antrum, duodenum, and colon. In 1993, Levine and Saul [23] suggested that idiopathic eosinophilic esophagitis should be considered in all patients with esophageal narrowing and a severe esophageal eosinophilia. These authors argued that the difference between the diagnosis of reflux esophagitis and idiopathic eosinophilic esophagitis depends on the location of the eosinophilia, with the implication that, in idiopathic eosinophilic esophagitis, esophageal eosinophils are located predominantly in the proximal esophagus and that the distal esophagus is spared. In contrast, a recent publication by Ruchelli [24 ] demonstrated that a diagnosis of eosinophilic esophagitis should be considered based on the degree of esophageal eosinophilia regardless of location. Ruchelli identified 102 patients who had at least one intraepithelial esophageal eosinophil after undergoing endoscopic biopsy for symptoms of gastroesophageal reflux. Patients initially underwent upper endoscopy with distal esophageal biopsy and were subsequently treated with aggressive antireflux pharmacologic therapy. Ruchelli s results indicate that the number of esophageal eosinophils/ HPF predicted patient improvement (1.1 ± 0.3), relapse (6.4 ± 2.4), or reflux treatment failure (24.5 ± 6.1). Clinical presentation The presentation of eosinophilic esophagitis in children is similar to the symptoms associated with gastroesophageal reflux. The majority of patients present with chronic epigastric pain and vomiting, regurgitation, or nausea (Table 1). Other uncommon symptoms include growth failure, hematemesis, dysphagia, globus, and water brash. In addition, nongastrointestinal symptoms occur in more than 50% of patients and include asthma, eczema, and chronic rhinitis. Adults present with similar symptoms; however, dysphagia occurs much more commonly and can be associated with esophageal strictures.

4 256 Pediatric Gastroentrology Table 1. Symptoms Associated with Eosinophilic Esophagitis Gastrointestinal COMMON Vomiting Epigastric pain Regurgitation Nausea LESS COMMON Growth failure Hemetemesis Dysphagia Globus Water brash Extra-intestinal Asthma Eczema Chronic rhinitis Table 2. Findings Suggestive of Eosinophilic Esophagitis Primary Severe eosinophilic esophagitis Secondary Reflux symptoms unresponsive to medical therapy Peripheral eosinophilia Presence of extra-intestinal symptoms (asthma, eczema, chronic rhinitis) Normal or borderline abnormal 24-hour ph probe testing Liacouras et al. [25 ] demonstrated that the clinical and histologic features of eosinophilic esophagitis may evolve over years. Of 20 children with eosinophilic esophagitis, five patients did not show a severe esophageal eosinophilia on initial endoscopy. Each of these patients, however, demonstrated a severe esophageal eosinophilia on repeat endoscopy after failure of antireflux medication. Similarly, while a peripheral eosinophilia occurred in all but six patients, it developed in five patients several months after initial evaluation. In all of these patients, esophageal histology demonstrated more than 20 eosinophils/hpf (Table 2). Finally, obtaining mucosal biopsies during endoscopy is paramount whenever EE is considered in the differential diagnosis (Fig. 1). The importance of obtaining biopsies during endoscopy was previously revealed by several investigators whose findings showed that even experienced endoscopists were not able to identify abnormalities demonstrated by histology [26,27]. In contrast, some investigators have suggested that endoscopic visual interpretation is more useful than histologic interpretation in children with chronic reflux symptoms because biopsies may be of limited help, especially in directing treatment of children with visually normal-appearing esophageal mucosa [28]. Recently, out of 35 cases of EE identified over the past 3 years at The Children s Hospital of Philadelphia, visual inspection of the esophagus was normal, while biopsy results showed a severe tissue eosinophilia consistent with EE. Biopsies should be obtained from the esophagus, stomach, and duodenum. Moreover, it is important to perform biopsies of other visually unaffected sites which may aid in diagnosis. Treatment Eosinophilic esophagitis has been shown to respond both clinically and histologically to a strict nonantigenic diet. In 1995, Kelly [29 ] reported on a group of children with esophageal eosinophilia who did not respond to antireflux therapy but instead improved on an amino-acid based formula. This Figure 1. Photographic image of esophageal biopsy in a 10-year-old child with eosinophilic esophagitis. study involved 10 patients with histologic esophagitis who were diagnosed with reflux esophagitis and who failed pharmacologic therapy. Six patients had a persistent esophageal eosinophilia despite undergoing a Nissen fundoplication. Only one patient had a 24-hour ph probe performed, which showed no evidence of reflux. 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, improvement in two). In addition, all 10 patients demonstrated a significant improvement in esophageal eosinophilia. Subsequently, all patients reverted to previous symptoms upon reintroduction of foods. While an exact etiology was not determined, Kelly suggests an immunologic basis, either a delayed hypersensitivity or a cell-mediated hypersensitivity response, as the cause for eosinophilic esophagitis. Eosinophilic esophagitis has also been shown to respond to corticosteroids. In 1998, Liacouras et al. [25 ] identified 20 of 214 patients presenting with symptoms and histologic abnormalities suggestive of gastroesophegal reflux disease who remained symptomatic despite the use of H 2 -blockers, proton pump inhibitors, and prokinetic agents [25]. All of these patients had an isolated severe eosinophilic infiltration of the distal esophagus (mean of 34±10 eosinophils/hpf) with normal antral/duodenal histology and minimal to no acid reflux by 24-hour ph probe monitoring. Upon introduc-

5 Eosinophilic Esophagitis: A Subset of Eosinophilic Gastroenteritis Liacouras and Markowitz 257 Table 3. Common Characteristics of Reflux Esophagitis and Eosinophilic Esophagitis in Children Reflux esophagitis Eosinophilic esophagitis Clinical Symptoms Epigastric pain, vomiting Epigastric pain, vomiting Key symptom Heartburn Dysphagia, odynophagia Gastroesophageal reflux Occurs in all cases Secondary occurrence ph probe results Usually abnormal Usually normal Histology Usually 0 3 eosinophils/hpf Usually >15 eosinophils/hpf Radiology May show reflux May show reflux Esophageal strictures Rare, usually distal Rare, usually mid Peripheral eosinophils < 5% of WBC Often >10% WBC (> 300/mm 3 ) Bronchospasm ± Microaspiration ± Systemic allergic disorder Systemic features No specific features Rhinitis, asthma, eczema Family history Not helpful Often history of family members with allergic disorders Treatment Acid blockade Clinical symptoms Usually effective Can improve secondary reflux symptoms Histologic abnormality Usually improves No significant improvement Fundoplication Effective for severe cases Not effective Dietary therapy Remove caffeine, tomatoes, spicy foods Any food can cause Food elimination trial Corticosteroids Not effective Almost always effective HPF high-powered field (40 ); WBC white blood cell count. tion of oral corticosteroids, 19 of 20 patients showed rapid improvement in clinical symptoms (average of 8 ± 3.5 days), and all 20 displayed histologic resolution of their esophageal eosinophilia within 1 month after being placed on corticosteroids. While corticosteroid therapy provides quick relief of symptoms and resolution of esophageal eosinophilia within 1 month, prolonged steroid therapy is not recommended. If symptoms recur soon after discontinuing steroid therapy (weeks to months), a strict elemental diet therapy should be instituted. However, if symptoms recur more than 1 year later, repeat short courses of corticosteroids are suggested. Several other treatment regimens have been reported. One case report in 1998 demonstrated rapid clinical improvement in four children with severe eosinophilic esophagitis after treatment with topical corticosteroids [30 ]. Patients were instructed to use inhaled corticosteroids but to immediately swallow after inhalation in order to deliver the medication to the esophagus. Histologic improvement was not determined. The mast-cell stabilizing agent cromolyn sodium has also been tried in children with EE. In similar fashion to its use for children with EG, oral cromolyn has been given to patients with a severe esophageal eosinophilia in conjunction with other systemic signs and symptoms of allergic disease. However, no controlled reports have been performed, and efficacy for oral cromolyn in children with EE has not been established. Surgical antireflux procedures are not effective in controlling patients with EE. Liacouras [31 ] documented two cases of failed Nissen fundoplication in patients with symptoms suggestive of gastroesophageal reflux unresponsive to aggressive antireflux medication. In both cases, the symptoms and abnormal esophageal pathology remained after surgery. Physicians should not assume that chronic distal EE results from acid reflux. In these cases, it is imperative that a 24-hour ph probe be performed, and, if results are markedly abnormal, antireflux surgery might be considered. On the other hand, if the ph probe is normal or mildly abnormal, then the diagnosis of EE is strongly suggested. Conclusions Children presenting with symptoms initially diagnosed as gastroesophageal reflux and esophagitis who continue to experience vomiting, regurgitation, dysphagia, or abdominal pain despite antireflux therapy should undergo repeat testing for eosinophilic esophagitis (Table 3). Eosinophilic esophagitis should always be considered when esophageal histology demonstrates more than 15 eosinophils/hpf or in patients with chronic esophagitis with eosinophils who demonstrate minimal reflux by ph probe criteria. This standard should prevent prolonged patient suffering, decrease patient morbidity, and replace unnecessary antireflux surgery with early appropriate therapy for EG. A single treatment is not effective in all patients. Patients with EE may represent various subgroups of eosinophilic enteritis. In some the disorder may be allergic in nature, in which case patients may respond to dietary manipulation. Others may involve immunologic or autoimmune defect and require the intermittent use of corticosteroids. In a recent editorial, Furuta [32 ] reviewed the pediatric literature related to the etiology, clinical presentation, and treatment of eosinophilic esophagitis. He suggested that the term idiopathic eosinophilic esophagitis be used until more definitive studies are performed. Thus, until an etiology is

6 258 Pediatric Gastroentrology determined, a standard pathologic definition is accepted, earlier clinical recognition occurs, and more acceptable long-term therapies are found, further research is required in this ever-increasing population of patients. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Wershill BK, Walker WA: The mucosal barrier, IgE-mediated gastrointestinal events, and eosinophilic gastroenteritis. Gastroenterol Clin North Am 1990, 21: Cello JP: Eosinophilic gastroenteritis a complex disease entity. Am J Med 1979, 67: Sawaya SM, Misk RJ, Aftimos GP: Eosinophilic gastroenteritis: report of two cases and comment on the literature. Eur J Surg 1992, 158: Vitellas KM, Bennett WF, Bova JG, et al.: Radiographic manifestations of eosinophilic gastroenteritis. Abdom Imaging 1995, 20: Moon A, Kleinman RE: Allergic gastroenteropathy in children. Ann Allergy Asthma Immunol 1995, 74: Brown K: Eosinophilic enteritis. In Clinical Pediatric Gastroenterology. Edited by Altschuler SM, Liacouras CA. Philadelphia: Churchill Livingstone; 1998: A textbook chapter discussing eosinophilic enteritis in children. 7. Katz AJ, Twarog FJ, Zeiger RS, Falchuk ZM: Milk-sensitive and eosinophilic gastroenteropathy: similar clinical features with contrasting mechanisms and clinical course. J Allergy Clin Immunol 1984, 74: Goldman H, Proujansky R: Allergic proctitis and gastroenteritis in children: Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol 1986, 10: Dobbins JW, Sheahan DG, Behar J: Eosinophilic gastroenteritis with esophageal involvement. Gastroenterology 1977, 72: Landres RT, Kuster GGR, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 1978, 74: Matzinger MA, Daneman A: Esophageal involvement in eosinophilic gastroenteritis. Pediatr Radiol 1983, 13: Lee RG: Marked eosinophilia in esophageal mucosal biopsies. Am J Surg Pathol 1985, 9: Teele RL, Katz AJ, Goldman H, Kettle RM: Radiographic features of eosinophilic gastroenteritis (allergic gastroenteropathy) of childhood. Am J Roentgenol 1979, 132: Picus D, Frank PH: Eosinophilic esophagitis. Am J Roentgenol 136: Feczko PJ, Halpert RD, Zonca M: Radiologic abnormalities in eosinophilic esophagitis. Gastrointest Radiol 1985, 10: Attwood SEA, Smyrk TC, Demeester TR, Jones JB: Esophageal eosinophilia with dysphagia: A distinct clinicopathologic syndrome. Dig Dis Sci 1993, 38: Ismail-Beigi F, Horton PF, Pope CE: Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970, 58: Behar J, Sheahan DC: Histologic abnormalities in reflux esophagitis. Arch Pathol Lab Med 1975, 99: Seefeld U, Krejs GJ, Siebenmann RE, et al.: Esophageal histology in gastroesophageal reflux. Morphometric findings in suction biopsies. Dig Dis Sci 1977, 22: Johnson LF, Demeester TR, Haggitt RC: Esophageal epithelial response to gastroesophageal reflux. A quantitative study. Dig Dis Sci 1978, 23: Winter HS, Madara JL, Stafford RJ: Intraepithelial eosinophils: A new diagnostic criterion for reflux esophagitis. Gastroenterology 1982, 83: Brown LF, Goldman H, Antonioli DA: Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis. Am J Surg Pathol 1984, 8: Levine MS, Saul SH: Idiopathic eosinophilic esophagitis: How common is it? Radiology 1993, 186: Ruchelli E, Wenner W, Voytek T, et al.: Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy. Pediatr Dev Pathol 1999, 2: Study demonstrating that the diagnosis of EE is dependent on the number of esophageal eosinophils/hpf. 25. Liacouras CA, Wenner WJ, Brown K, Ruchelli E: Primary eosinophilic esophagitis in children: Successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998, 26: First article demonstrating clinical features, successful corticosteroid therapy, and follow-up in children with EE. 26. Biller JA, Winter HS, Grand RJ, Alred EN: Are endoscopic changes predictive of histologic esophagitis in children? J Pediat 1983, 103: Leape LL, Bhan J, Ramenofsky ML: Esophageal biopsy in the diagnosis of reflux esophagitis. J Pediatr Surg 1981, 16: Hassall E: Macroscopic vs microscopic diagnosis of reflux esophagitis: erosions or eosinophils. J Pediatr Gastroenterol Nutr 1996, 22: Kelly KJ, Lazenby AJ, Rowe PC, et al.: Eosinophilic esophagitis attributed to gastroesophageal reflux: Improvement with an amino acid-based formula. Gastroenterology 1995, 109: First article demonstrating the response of children with chronic esophagitis (eosinophilia) to dietary therapy with an amino-acid based formula. 30. Faubion WA Jr, Perrault J, Burgart LJ, et al.: Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998, 27: Case report on four patients with EE treated with inhaled corticosteroids. 31. Liacouras CA: Failed Nissen fundoplication in two patients who had persistent vomiting and eosinophilic esophagitis. J Pediatr Surg 1997, 32: Case report on two patients with reflux symptoms unresponsive to anti-reflux medication who failed fundoplication and were later diagnosed with EE. 32. Furuta GT: Eosinophils in the esophagus: Acid is not the only cause. J Pediatr Gastroenterol Nutr 1998, 26: Editorial discussing the role of the eosinophil in the esophagus and comparing EE to gastroesophageal reflux.