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Do Eosinophil Numbers Differentiate Eosinophilic Esophagitis from Gastroesophageal Reflux Disease?

Muriel Genevay, MD; Laura Rubbia-Brandt, MD, PhD; Anne-Laure Rougemont, MD

Context.Although the healthy esophageal mucosa conN tains no eosinophils, eosinophilic infiltration is observed in 2 major clinicopathologic settings: gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EE). The prevalence of EE is increasing in many countries, and this increase seems only partly to be due to a better awareness of the pathology, following the relatively recent description of EE. Gastroesophageal reflux disease and EE represent 2 entities that do not respond to the same treatment modalities and, thus, need to be distinguished. However, diagnostic criteria of EE have been defined arbitrarily, and the more recent articles tend to prove that the overlap with GERD is probably greater than initially believed, leading the authors to advise strict exclusion of GERD before considering the diagnosis of EE. Objectives.To provide pathologists with the currently proposed histologic criteria of GERD and EE, to stress the astroesophageal reflux disease (GERD) and eosinoG philic esophagitis (EE) are the 2 most common nonneoplastic esophageal conditions that may require endoscopic examination in both children and adults.1 The incidence of both entities is increasing. Because of considerable clinical and histologic overlap between these 2 conditions, definitive diagnosis usually requires clinicopathologic correlation. Moreover, the 2 pathologies may coexist.2 Gastroesophageal reflux disease is extremely common, with an incidence of 10 to 20% in Western adults presenting with reflux symptoms and heartburn3 and is the most common disease in patients referred for upper endoscopy.4 Eosinophilic esophagitis is an emerging disease that has been more precisely defined by recent reviews and consensus studies. Notably, the incidence of these 2 diseases has increased recently.4 The pathologist responsible for the evaluation of esophageal biopsies has to be aware of the existence of the 2 entities and their common histologic overlap and that a definitive diagnostic will rarely be based solely on microscopic features. Their distinction is, however, imAccepted for publication June 17, 2009. From the Department of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Muriel Genevay, MD, Service de Pathologie Clinique, Centre Me dical Universitaire, 1 Rue Michel Servet, CH-1211 Gene ` ve, Switzerland (e-mail: Arch Pathol Lab MedVol 134, June 2010

need to combine these criteria with clinical data and endoscopic findings, and to outline the remaining controversies. Data Sources.This review is based on selected articles identified by a PubMed (US National Library of Medicine, Bethesda, Maryland) search of the literature in English for GERD and EE, a recent review by the American Gastroenterological Association (Bethesda), the Proceedings of the First International Gastrointestinal Eosinophil Research Symposium, and the authors experience. Conclusions.Proper identification of the etiology of eosinophilic infiltration of the esophagus allows accurate medical or surgical treatment and follow-up. Eosinophilic esophagitis and GERD diagnoses require integration of the histologic findings with the clinical and endoscopic data. (Arch Pathol Lab Med. 2010;134:815825) portant because of different clinical outcomes and treatment modalities, notwithstanding the improved quality of life for the patient. Given this setting, we have decided to emphasize the considerable morphologic and clinical overlap between GERD and EE, and our intention is to identify diagnostic clues. In each of the following paragraphs, we will, therefore, report the aspects of the 2 clinicopathologic entities, separately whenever adequate, and will provide a summary of the most relevant features. This review is focused on the most relevant articles addressing this differential diagnosis and is not intended to be exhaustive. DEFINITIONS Eosinophilic Esophagitis Eosinophilic esophagitis is a primary eosinophilic gastrointestinal (GI) disorder characterized by eosinophilic infiltration of the GI tract and is not related to a specific etiology.5,6 Eosinophilic esophagitis was first described in 1978 by Landres et al,7 in a patient with achalasia, and it was interpreted as a variant of eosinophilic gastroenteritis, although the histology of the rest of the GI tract was not reported, and then by Forget et al8 in an infant. In 1985, Lee9 reported on a series of patients with marked eosinophilic infiltration of the esophagus, some of which were in an allergic setting. In 1993, EE was defined as a specific clinicopathologic entity.10 Since then, the increase in the diagnosis of patients with upper GI symptoms who have dense esophageal eosinophilia and do not respond to antiacid treatment has allowed better recognition of EE. In
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2007, a consensus meeting of the American Gastroenterological Association Institute and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommended diagnostic criteria in EE.11 Eosinophilic esophagitis was defined as a clinicopathologic entity, combining clinical data on (1) relevant symptoms (distinct in the pediatric or adult populations, with mostly food impaction and dysphagia in adults and feeding intolerance, failure to thrive, and GERD symptoms in children); (2) esophageal biopsies with adequate histologic findings in the esophageal biopsies ($15 eosinophils/ high-power field [HPF]); and (3) exclusion of other diseases with overlapping features, especially GERD.11 Notably, the esophagus symptoms and dense eosinophilic infiltrate of EE persist despite the use of proton pump inhibitors (PPIs). In the recent Summary of the First International Gastrointestinal Eosinophil Research Symposium,1 resistance to PPI therapy was considered a diagnostic criteria. An absence of eosinophilic infiltration in other segments of the GI tract is also required, thereby, distinguishing EE from eosinophilic gastroenteritis, another eosinophilic GI disorder.5 Gastroesophageal Reflux Gastroesophageal reflux is the passive flow of gastric content back into the esophagus. Gastroesophageal reflux leads to GERD when symptoms or evidence of organ damage, as reported for the esophagus, larynx, tracheobronchial tree, or lung, are present.12 The esophagus, the principal target of gastroesophageal reflux, can develop as either a reflux (erosive) esophagitis (ERD) or as a nonerosive esophagitis (NERD).12 Whether typical symptoms are sufficient to be diagnostic or endoscopy or histologic diagnosis of esophagitis is needed remains a source of debate. pH monitoring is the most specific test, but it lacks sensitivity. EPIDEMIOLOGY AND CLINICAL MANIFESTATIONS Eosinophilic Esophagitis The prevalence of EE has been increasing worldwide.1315 However, some authors have attributed this increase to a better recognition of EE.16 Eosinophilic esophagitis has a pediatric predominance; most adult patients come to clinical attention during their third or fourth decades.17 Males are affected more often than females in both the pediatric and adult populations, with a male to female ratio of 3:1 to 4:1.17,18 A recent, random, adult population-based study performed in Sweden identified esophageal intraepithelial eosinophils in nearly 5% of the examined population, and definite EE (defined in the study as $20 eosinophils/HPF) in 0.4% of the subjects.19 Other reports cite prevalence of 1 in 1500 in the pediatric population,20 and prevalence in adults rising from 2 to 23 in 100 000 during a 16-year period in the Swiss population.15 A strong familial association has been observed in up to 10% of the patients.1 Adults commonly present with food impaction, intermittent dysphagia, or with symptoms also encountered in GERD, such as heartburn, reported in up to 24% of patients.21 Frequently, the patients have long-standing symptoms before the diagnosis is made. In addition, children can present with irritability, feeding intolerance, failure to thrive, vomiting, regurgitation, and epigastric or chest pain.22 With increasing age, their symptoms become similar to those of adults.
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Not uncommonly, the patients display peripheral eosinophilia, increased immunoglobulin E levels, and elicit a personal or familial history of allergy, including asthma and food allergies.18,22 Gastroesophageal Reflux If frequency of heartburn, the cardinal symptom of GERD, is considered diagnostic, then GERD can be observed in up to 20% of the general population in Western countries and in 22% of patients requiring an upper endoscopic examination.4 Gastroesophageal reflux disease is reported in 2% to 7% of the pediatric population.23 In adults and in children, a male predominance is observed, and symptoms appear earlier in men than in women.4,24 Gastroesophageal reflux is common in infancy, with daily regurgitations observed in half of the children younger than 3 months, whereas vomiting is occasional.25,26 However, complete resolution of symptoms occurs in 60% to 80% of infants by 18 months of age and in 98% by 2 years.25 Only a minority of infants will develop GERD, with potential failure to thrive, irritability, dysphagia, and respiratory complications (such as aspiration pneumonia) or chronic cough.26 The risk factors in adults include the use of nonsteroidal anti-inflammatory drugs,4 obesity, alcohol, tobacco, and eradication of Helicobacter pylori, mainly in patients with atrophic corpus gastritis,27,28 although is still being debated.29 Hiatus hernia seems to be responsible for more severe esophagitis.3032 A genetic influence is described in almost 30% of patients with GERD.33 Heartburn is often considered diagnostic in itself and is defined as a substernal pain increasing during exercise or on lying down.34 Other symptoms can be separated in 2 groups of typical (acid regurgitation and dysphagia) and atypical (mainly chest pain, asthma, cough, and hoarseness) symptoms.35 Summary Among confusing clinical features, heartburn can be a symptom of EE, and dysphagia can also be observed in GERD. However, the symptomatology sequence differs between the 2 entities: dysphagia is a late complication of GERD, whereas food impaction and dysphagia most frequently inaugurate EE in the adult population. Similarly, reflux esophagitis can be a late complication of EE caused by dysmotility in a fibrotic esophagus. The distinction between the clinical symptoms of GERD and EE is even more blurred in the pediatric population, especially in infants younger than 18 months. These elements stress the role of a PPI treatment trial as a diagnostic test.1 In the pediatric population with resistance to PPI treatment, the prevalence of EE is 68% to 94%.36 This overlap can, however, be due to coexistence of GERD and EE, whether by chance or because one entity induces the other.2 ENDOSCOPIC ASPECTS AND FUNCTIONAL TESTS In both pathologies, upper endoscopy will not only provide diagnostic clues but also allow clinicians to assess the severity of the changes and the response to therapy and, thus, document remission and evaluate recurrence.1 In addition, endoscopic biopsies will rule out alternate diagnoses, such as Candida infection or connective tissue disease.37
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Esophageal manometry, which evaluates motor function, may show nonspecific esophageal dysmotility in a few patients.13,17,44 Endoscopic ultrasound techniques can document thickening of the esophageal wall mainly resulting from intense eosinophilic infiltration or from fibrosis.44 To date, although counting peripheral eosinophils and determining total immunoglobulin E levels help in the assessment of atopy, the exact role of these tests remains to be defined as disease or severity markers in EE.11 Notably, concurrent atopy in patients with EE represents an important confounding factor.11 Gastroesophageal Reflux The absence of correlation between clinical symptoms and endoscopic findings, as well as between endoscopy and histologic features, is a particularly striking features of GERD.49 Consequently, some believe that GERD should only be assessed clinically.50 However, even if a diagnostic questionnaire was developed,51,52 clinical information alone cannot be reliably trusted in children because the rate of false-positive cases can be as high as 81%.53 Patients tend to be divided in 3 groups according to endoscopy, as follows: (1) NERD (35%67%), (2) ERD (50%65%), and (3) intestinal metaplasia (Barrett esophagus) (4%).4,12,50,54 Typical associated reflux erosions or ulcer are situated near the Z line, on the top of the mucosal folds; more confluent lesions lessen the diagnostic value of this finding.55 It is usually admitted that a progression exists between these 3 different expressions of the disease spectrum.34 However, some authors pretend that this endoscopic stratification, usually made at the time of the initial biopsies, appears to be stable over time.4 Notably, there is a higher frequency of ERD, as opposed to NERD, with increasing age.4,56 Less than 50% of the adult patients younger than 50 present with ERD,4,24 whereas between 12.4% and 60% of the pediatric patients present with ERD.49,56 Endoscopy results are always normal in patients younger than 4 months,49 whereas ERD is observed in 5.5% of children younger than 1 year, and the prevalence increases to 19.6% by age 17.56 In the later series, the presence of hiatus hernia was the only predictive factor of ERD.56 In NERD, the esophageal mucosa appears healthy in up to 50% of cases, or it may show minimal changes, such as diffuse erythema, whitish exudates, friability, or a cobblestone pattern. All these endoscopic findings are observed near the Z line, can be very subtle, and have a very poor interobserver reproducibility. With increasing disease severity, true erosions appear and become more confluent with pathology evolution. The presence of a whitish exudate appears to be a sign of severity that correlates well with the duration of acid exposure as measured by pHmetry.57 Multiple classification systems have been established to score the severity of esophagitis. Three main GERD classifications are in use. The Los Angeles classification is based mainly on the presence of erosions, and it offers no distinction between the different types of complications.58 Los Angeles GERD appears to be the most reproducible.59 The Savary-Miller classification, mainly used in Europe, reports both erosions and complications, such as ulcers, Barrett esophagus, and strictures.60 The MUSE (metaplasia, ulcer, stricture, erosion) classification reports complications and allows differential diagnosis between metaplasia, ulcers, and strictures, as well as a grading of erosions and each complication separately.58
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Figure 1. Typical esophageal narrowing and ring formations in a patient with eosinophilic esophagitis.

Eosinophilic Esophagitis A normal endoscopic examination is observed in 10% to 25% of adult patients and in 26% to 32% of children with EE.17,3739 Findings include vertical furrowing and strictures (both mostly occurring in the superior two-thirds of the esophagus), white plaques, speckles, or exudates (to be distinguished from Candida infection), longitudinal shearing following passage of the endoscope in a fragile or pe esophagus, a narrow caliber esophagus, papier cre and fixed or transient rings or esophageal trachealization (Figures 1 and 2, A).13,4042 These endoscopic findings are not pathognomonic, but a narrow esophageal lumen, associated with concentric rings, with or without proximal stenosis of the esophagus, is highly suggestive of EE.40 Strictures are rare in children but are present in 40% to 50% of adult patients.13,17 Fragility and edema of the esophagus are classically described in EE, and a risk of tearing exists following dilatation,11,13 whereas perforation has been described in one patient.43 Adjunct tests that may be used in distinguishing EE and GERD are 24-hour pH probe tests, esophageal manometry, and endoscopic ultrasound.44 Intraesophageal pH testing yields normal results in 82% of adult patients with EE and 90% of pediatric patients.11 Unless coexistence of GERD represents a confounding factor, as has been reported in a few cases, the pH probe test results should be normal or only slightly abnormal in patients with EE.4547 Among 40 patients with histologic findings of more than 20 eosinophils/HPF, Rodrigo et al47 retained an EE diagnosis in only 6 patients (15%), whereas 2 patients (5%) had coexistent EE and GERD, and 28 patients (78%) had GERD. In that series, the stratification of patients was based on clinical symptoms, endoscopic findings, videoesophagram results to detect caliber changes, pH monitoring, and manometric studies.47 To further stress the possible coexistence of GERD and EE, symptomatic and histologic relief was provided by PPI in 3 symptomatic children with endoscopic features of furrowing and white exudates, as well as high mucosal eosinophil counts (.20 eosinophils/HPF), all suggestive of EE.48
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Figure 2. Schematic representation of the main endoscopic findings of eosinophilic esophagitis (A) and gastroesophageal reflux disease (B).

The interobserver reproducibility is comparable to that of the Los Angeles classification.59 The modified Los Angeles system, designed to integrate minimal changes of NERD and considered to represent a distinct grade of esophagitis,61 has been discouraged following evidence of poor interobserver reliability.6163 pHmetry is considered an important procedure in the diagnosis of pathologic gastroesophageal reflux. It allows better characterization of the reflux and differentiation between reflux arising in an upright or supine position, the latter with more long-lasting episodes. It also shows that mean esophageal acid contact time is greater in patients with GERD than in healthy subjects and is greater in ERD than in NERD.12 However, this test is not sensitive, especially in the pediatric population, with as many as 53% of patients with abnormal histologic findings having normal findings in the pH study.53,64 The poor sensitivity could be explained by esophageal lesions induced by isolated bile reflux,64 and the use of combined acid and bilirubin monitoring is recommended to increase diagnostic sensitivity.64 Summary Distinction between EE and GERD is mostly problematic in cases of NERD because erosions and ulcers are infrequent in EE. The relevant endoscopic findings of EE and GERD are represented in Figure 2, A and B. HISTOLOGY In both EE and in GERD, the histologic evaluation provides diagnostic clues, allows assessment of the severity of disease, documents response to therapy, and suggests possible complications. Biopsy and histology are manda818 Arch Pathol Lab MedVol 134, June 2010

tory for a diagnosis of EE with biopsies recommended in patients with suspected EE, even when the mucosa appears healthy.37 In GERD, histologic evaluation improves the sensitivity of endoscopy in detecting esophagitis. Unlike the rest of the GI tract, the normal esophageal mucosa harbors no eosinophils, and infiltration of the squamous epithelium by eosinophils represents a sign of esophagitis. Esophageal eosinophilia can be separated into primary or idiopathic disorders, which may be atopic or familial, and secondary to inflammation, infections (mainly fungal), or an atopic condition.6 There exists no absolute histologic criterion allowing definitive distinction between EE and GERD, and cutoff values for numbers of eosinophils vary according to studies and authors. Basal cell hyperplasia, intercellular edema, and elongation of the epithelial papillae all occur in both EE and GERD.38,65 Eosinophilic Esophagitis Eosinophilic esophagitis is a patchy disease, and adequate evaluation, thus, requires multiples biopsies.18 Eosinophilic infiltration has been reported as predominant in various, and often contradictory, locations37,44; sampling of the upper, mid, and distal esophagus is recommended.44 Moreover, focal lesions are described in up to 50% of cases.44 The peak eosinophil count is the leading point, not the location of the mucosal eosinophilia,22 and the diagnostic criteria are similar in adults and children.11 Biopsies from the antrum and duodenum should also be performed to exclude an eosinophilic gastroenteritis, which represents a different clinicopathologic entity.6 Crohn disease can also induce an eosinophilic infiltration of the esophagus and should be ruled out.
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produced by biopsy processing.1 Fibrosis of the lamina propria has also been reported and is related to dysphagia, food impaction, and severe histologic disease.38,41,67,68 An alternate diagnosis should be sought in the presence of erosions or neutrophilic infiltration. Gastroesophageal Reflux The correlation between the endoscopic features of GERD and histology is poor, especially in cases of nonerosive disease. This has lead some authors to consider histology as nonmandatory69 and others to recommend biopsies only to rule out another pathology.55 Histologic esophagitis is present in only 27% of patients with clinical GERD, and 22% of patients with no clinical criteria of GERD display histologic esophagitis.50 However, when papillary elongation, basal cell hyperplasia, and enlargement of the intercellular space are considered as signs of esophagitis, histology can dramatically improve the sensitivity of endoscopy.70 Classically, 4 biopsies are recommended, with 2 biopsies taken near the Z line, and 2 taken 2 cm above the Z line.70 In NERD, the morphologic findings are subtle and nonspecific. Abnormal histologic features are observed in 35% of infants with a normal endoscopy.49 Esophagitis is defined histologically by basal cell hyperplasia, increased papillary length, and infiltration by polymorphonuclear neutrophils or eosinophils. At least 2 of these findings are mandatory for a positive diagnosis of esophagitis,70 but these are neither specific nor sensitive for the diagnosis of GERD.50,71 Basal cell hyperplasia and papillary elongation were first reported by Ismail-Beigi et al,72 and have long been considered one of the most reliable criteria in the diagnosis of early GERD. To be diagnostic, the basal cell layer has to represent more than 15% to 25% of the total epithelial thickness, and the top of the papillae has to reach the upper third of the epithelium.73,74 However, adequate biopsy orientation, as well as a large specimen, is required for certainty of assessment. Basal cell hyperplasia, when morphometrically measured, seems to represent the most sensitive feature, whereas papillary elongation and dilated intercellular spaces are the most specific for esophagitis, whatever the cause.49,70,74 Basal cell hyperplasia and papillary lengthening have both been shown to correlate with the duration of exposure to acid secretions.74 Recent studies have shown, however, that 70% of patients with abnormal pH monitoring showed no basal cell hyperplasia.50,75 Dilated intercellular spaces correspond to enlargement of the intercellular spaces69,76 and correspond to a break in the epithelial barrier (best seen with transmission electron microscopy) and, as such, are probably a precursor of erosion.12 Dilated intercellular spaces may represent an early sign of esophagitis, but it has also been seen in EE, in Candida infections, and in up to 30% of healthy controls.77 Dilated intercellular spaces are observed in 68% to 100% of patients with acid exposure; bile reflux can also lead to the development or persistence of dilated intercellular spaces.77 Assessment of dilated intercellular spaces is possible by optical microscopy with good sensitivity.70 (Histologic findings of GERD are illustrated in Figure 3, B.) The excellent correlation between endoscopy findings and histology in patients with ERD lessens the importance of pathology in these patients.70 However, in the pediatric population, 10% of patients show severe histologic inflammation in the absence of endoscopic lesions, and
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Figure 3. A, Histologic findings consistent with eosinophilic esophagitis. Intense eosinophilic infiltration with superficial layering, basal hyperplasia (.50% of total epithelium thickness), and dilated intercellular spaces. Superficial eosinophilic microabscess, with eosinophil degranulation and dilated intercellular spaces (inset). B, Findings consistent with gastroesophageal reflux disease with basal cell hyperplasia, papillary elongation, and scattered eosinophils (hematoxylin-eosin, original magnifications 3200[A], 3400 [inset], and 3100 [B]).

Although reports of eosinophil numbers required for the diagnosis of EE vary widely, an actual counts needs to be performed. In the American Gastroenterological Association consensus recommendations, a peak eosinophil count of more than 15 per HPF (3400) is required for the diagnosis of EE.11 Preferential eosinophilic localization in the superficial portions of the esophageal epithelium and formation of eosinophilic microabscesses, defined as clusters of 4 or more eosinophils, are also diagnostic clues.66 Figure 3, A, illustrates the histologic findings of EE. Degranulating eosinophils are also frequently observed.44 Necrotic membranes composed of sloughed squamous cells intermingled with eosinophils provides the histologic correlate to the endoscopic white speckles,44 despite overall poor correlation between endoscopic and histologic severity. Basal cell hyperplasia in EE is correlated with the density of intraepithelial eosinophil and mast cell infiltration, at least in children, and can occupy more than 50% of the epithelial thickness.20,38,65 Papillary elongation of the lamina propria (ie, when the papillae exceed 75% of the epithelium thickness) is frequently observed. Basal cell hyperplasia, papillary lengthening, and dilatation of intercellular spaces also correlate with eosinophil degranulation67; however, the latter feature that can also be
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5% with significant endoscopic findings have no histologic inflammation.54 Moreover, less enthusiastic results were provided by Chadwick et al,49 who reported normal histologic findings in 35% of children with severe esophagitis, arguing that the pathologic areas were probably not biopsied. Intraepithelial eosinophils are found in 50% to 60% of pediatric patients78 and in 30% to 50% of adults79,80 with GERD and are more prevalent in the presence of erosions or mucosal breaks.78 The numbers of inflammatory cells per HPF increases with age between 0 and 24 months and correlates with an increase in endoscopically detected esophagitis.78 In GERD, eosinophil numbers are classically supposed to be less than 7 per HPF.81,82 A strong correlation is observed between the number of intraepithelial eosinophils and the endoscopic or histologic severity of the lesions.54,78 The presence of intraepithelial lymphocytes could be an early marker of esophagitis in young infants, although the presence of these cells in healthy controls limits their diagnostic value.49 Summary Basal cell hyperplasia, papillary elongation, and dilated intercellular spaces are markers of esophagitis, whatever the etiology. Basal cell hyperplasia appears more frequently and more severely in EE.75 Eosinophilic infiltration is observed in both EE and GERD, and if eosinophils are supposed to be less abundant in GERD, a specific cutoff value is not available. Numbers lower that 5 or higher than 20 eosinophils per HPF are nonetheless highly suggestive of GERD and EE, respectively. However, even superficial eosinophilic clustering and microabscesses are not entirely specific for EE.47 Suggestive histologic findings are integrated in a schematic representation (Figure 4, A through C). Based on the data in the literature and our own experiences, we recommend taking into account the peak eosinophil count, whatever the esophageal biopsy location. Morphology alone seems adequate for eosinophilic count, provided that biopsies are adequately fixed in buffered formalin. This peak count should be mentioned in the histology report, together with a description of other histologic criteria, whether present or absent, as summarized in Figure 4, A through C. A peak eosinophil count of more than 15 per HPF (especially during PPI therapy), or of less than 5 per HPF (3400; 0.44mm2 field) may be interpreted as consistent with EE and GERD, respectively, although we believe that a note such as in an adequate clinical setting should also be added. PHYSIOPATHOLOGY AND IMMUNOLOGY Eosinophils are proinflammatory and immunomodulatory cells that accumulate in the GI tract in a variety of disorders and, most notably, in atopic patients.83 Release of cationic proteins from eosinophil granules, including eosinophil-derived neurotoxin and eosinophil peroxidase, causes direct or leukotriene-mediated epithelial injury.84 Eosinophilic Esophagitis The etiology of EE has not been fully elucidated, and hypotheses are centered on an immunoallergic basis. A short report, in the form of a Letter to the Editor, 85 provided evidence for seasonal variation both in symptoms and histology and for density of eosinophilic infiltration. A relationship to pollen was postulated. The role of aeroallergens in the development of EE in sensitized atopic
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patients has been addressed, and it has been shown in a murine model that inhalation of respiratory allergens can induce marked EE with allergic responses elicited in the lungs and the esophagus, whereas the stomach and bowel remained devoid of eosinophils.86 Eosinophilic esophagitis is related to helper T cell (TH2) immune processes,87 with interleukin (IL) 4, IL-5, and IL-13 playing an important role 5 Interleukin 5 is a major regulator of eosinophils, specifically inducing their production and activation and is involved in tissue recruitment as well, via the induction of adhesionmolecule expression with increased adhesion of eosinophils to endothelial cells.88 Overexpression of IL-5 is observed in the esophagus of patients with EE.87 Interleukin 4 and most IL-13 are produced in high quantities by TH2 cells in the lungs of asthmatic patients and regulate multiple aspects of the allergic response. Interleukin 13 delivery to the lung in mice induces EE and provides a link between lung and esophagus eosinophilia and hypersensitivity responses.89 A genomewide expression profile has been established in esophageal specimens of patients with EE and has been compared with that in patients with chronic esophagitis, including GERD, and to healthy controls.20 That study identified a transcript signature highly conserved among patients, with only a differential expression of 1% of the genome transcripts between biopsy samples from patients with EE and controls. The authors speculated that this transcript signature represented a dysregulation in transcription. Of note, a nearly complete overlap was observed between allergen-sensitized and nonatopic patients with EE, suggesting a common pathogenesis. Eotaxin-3 was the most highly induced transcript, being increased 53-fold, and susceptibility to EE was associated with a single nucleotide polymorphism in the eotaxin-3 gene.20 A further study provided evidence that apart from an increase in eotoxin-3, patients with EE also displayed elevated levels of eotoxin-1 and eotoxin-2, CCR3, and IL-5.66 CCR3 is an eotaxin receptor that is also expressed on mast cells.90 A role for mast cells in EE has been postulated, following the observation that levels of esophageal mast cell infiltration correlate with eosinophil infiltration and with the degree of basal cell hyperplasia.20,91 Mast cell infiltration, which might precede eosinophilic infiltration, liberates chemoattractant molecules that recruit eosinophils, which further induce esophageal tissue damage, in turn, increasing mast cell degranulation.84 An immunohistochemical study showed an increase in CD3 and CD8 T lymphocytes in the esophageal mucosa of patients with EE, together with an increase in the antigenpresenting CD1a+ Langerhans cell population,92 compared with healthy controls, but patients with GERD were not evaluated in this study. However, this finding has also been described in GERD as a potentially secondary phenomenon.93 Stricture formation is a well-established complication of EE and is preceded by lamina propria fibrosis and esophageal remodeling. Fibrosis of the lamina propria might be explained by mechanisms involving TGF-b1 and activation of its downstream signaling molecule, phosphorylated Smads 2 and 3.68 Mast cells also induce fibrogenesis via histamine and tryptase-mediated pathways. Vascular density of the lamina propria is also increased in patients with EE, compared with both patients with GERD and with healthy controls and is possibly related to endothelial activation and expression of vascular cell adhesion molecule 1.68
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Figure 4. Schematic representation of the characteristic histologic findings of eosinophilic esophagitis (A), gastroesophageal reflux disease (C), and cases with overlapping features (B). Abbreviation: HPF, high-power field (original magnification 3400).

Finally, the few instances of familial clustering of EE94,95 suggest a potential genetic predisposition. Gastroesophageal Reflux Reflux is a physiologic phenomenon, which becomes pathologic when protective mechanisms are overcome. Neither the frequency nor the severity of the reflux predicts the presence of erosive esophagitis or the later development of strictures. The development of GERD is the consequence of a cascade of events resulting in epithelial damage, and complications result from an inappropriate response to
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epithelial damage. The squamous epithelial damage is the consequence of exposure to noxious agents (mainly gastric acid and pepsin but also to bile and duodenal content) and/or to a defect in the mechanisms involved in squamous mucosa defence.12,64 Exposure results from a defect in antireflux mechanisms that include anatomic barriers such as the lower esophageal sphincter and the diaphragm.12,33 Lower esophageal sphincter dysfunction can be explained by lower esophageal sphincter pressure abnormalities, including abnormal transient relaxation.33 This pressure can be decreased by foods (high fat meals, chocolate, and caffeine), alcohol, and smoking, as well as
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by hormones (eg, progesterone during pregnancy).12 Hiatus hernia is a major factor of lower esophageal sphincter dysfunction.33 Other protective mechanisms include luminal clearance, dilution, and neutralization of acid content by salivary and esophageal secretions. Tissue resistance itself comes from apical cell membranes, intercellular junctional complexes, and buffers present in the intercellular space and extruding from the blood supply.12 These protective mechanisms are insufficient when acid secretion lowers the pH to less than 3.0. The enlargement of the intercellular spaces is a sign of epithelial damage and could represent an explanation for heartburn by allowing contact between acid reflux and nociceptor neurons,12 although that remains to be proven.77 The exposure of the esophageal epithelium to reflux induces a paracellular permeability that results morphologically in dilated intercellular spaces, which can be seen in both ERD and NERD.33 Diffusion of the reflux in intercellular spaces leads to cell edema and necrosis, followed by epithelial repair, which is mediated by salivary epidermal growth factor.33 Hiatal hernia is further strongly associated with Barrett esophagus and with more severe GERD.33 The third line of mucosal defense is the reparative capacity of the mucosa with restitution and replication.12 It has been shown that the more severe the endoscopic appearance, the less the basal cell layer was able to proliferate.69 This can be due to either modifications of the replicative activity of cells or to genetic characteristics.69 Elevated eotaxin-3 RNA levels have been reported in paraffin-embedded, esophageal biopsy tissues in patients with GERD compared with healthy controls but at significantly lower levels than in patients with EE.66 The authors hypothesized that eotaxin3 also plays a role in eosinophil recruitment in GERD.66 Summary Elevated oetaxin-3 levels in the esophagus and in blood might help separate EE from GERD.20,66 Mast cell numbers are correlated with severity of eosinophilic infiltration in EE but are not usually present in GERD.91 Cytokines and adhesion molecules involved in eosinophilic chemoattraction in EE also have a role in tissue eosinophilia in patients with GERD. TREATMENT Eosinophilic Esophagitis The aim is to maintain patient quality of life with lesser side effects. Controversies relating to treatment endpoint exist. Should symptoms or tissue eosinophilia be treated11? When left untreated, clinical manifestations of EE vary considerably, ranging from permanent resolution to progression, and either fixed or stable disease. Medical strategies are not well standardized and have adverse effects, whereas restrictive diets significantly alter quality of life.11 Regular clinical follow-up is mandatory for both children and adults.11 Repeated endoscopy could help assess the clinical and histologic response in asymptomatic patients with persistent eosinophilia or after institutional or treatment modification (usually within 4 weeks).11 Acid suppression is recommended, along with a 4- to 6week trial of PPI.5,48,96 Persistence of symptoms lends further support to a diagnosis of EE. Patients with welldocumented EE may develop gastroesophageal reflux
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symptoms that will probably respond to PPI, but PPI should not, however, be considered a primary treatment option.11 Elimination of food allergens allows clinical and histologic improvement in most patients, providing supportive evidence that antigens are eliciting the disease. Consequently, consultation with a dietician is strongly recommended and allows taking into consideration personal lifestyle.11 More drastically, a 4-week trial period of elemental diet is effective in EE, allowing both symptomatic and histologic relief.97 Improvement of EE had been shown with an amino acidbased formula (such as Neocate, Nutricia North America, Gaithersburg, Maryland), even in patients with GERD symptoms and an abnormal findings from pH monitoring.98 However, compliance to this treatment is difficult to achieve. It has been suggested that combining skin prick and atopy patch tests to exclude from the diet both the involved food products and milk leads to clinical and histologic resolution in about 70% of patients with only the remaining patients requiring a semielemental diet.99 An evaluation of food allergy should thus be undertaken in all patients, allowing an adequate diet.100 Dilatation has to be considered with caution, because esophageal tears of a fragile and edematous mucosa have been described and might also be related to simple passage of the endoscope.13,40,43 Medical treatment classically relies on topical corticosteroids for long-term disease control or systemic corticosteroids for acute episodes.6,101 Although a few patients exhibit histologic resolution, symptom recurrence is often observed following interruption of the treatment.102 Topical application relies either on swallowed steroid either as a viscous budesonide, obtained by mixing budesonide inhalation suspension, with sucralose,68 or administered through a metered-dose inhaler, used without a spacer to allow significant delivery to the esophagus.45,103 A randomized, placebo-controlled study104 confirmed that swallowed steroid (fluticasone propionate) was indeed efficient, with histologic remission in about 50% of patients with EE. Response to therapy was greater in nonallergic than in allergic patients. Histologic remission was defined as identification of less than one eosinophil in all HPFs in the proximal and distal esophagus. Treatment options with cromolyn (a mast cell stabilizer) or with omalizumab (an antiimmunoglobulin E) have not as yet proven efficient in EE.5,101 Montelukast, a leukotriene receptor antagonist, allows subjective symptom relief, with relapse after treatment interruption; notably, no change in the density of eosinophilic infiltration was observed after treatment.105 In a series of 3 adult patients with severe disease, antitumor necrosis factor a with infliximab yielded a heterogeneous response, but allowed correction neither of the eosinophilic infiltration nor of the symptoms.106 Selective therapeutic targeting of IL-5 has yielded promising results.107109 Mepolizumab treatment allowed symptom and endoscopic amelioration, a sustained decrease in peripheral blood eosinophil and CCR3+ cell levels, as well as a significant decrease in esophageal eosinophilia. However, eosinophil numbers remained high.107 Gastroesophageal Reflux Until recently, treatment was initiated only when erosive esophagitis was present, but the generalization of the use of PPI has led to treatment of the symptoms, rather than the esophagitis.34 Proton pump inhibitors are efficient in alleviating symptoms, and in improving
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esophagitis. Proton pump inhibitors have to be given 15 to 30 minutes before meals to provide the highest concentration at the time of stimulation by food intake.110 Only 20% of patients with resistance to PPI therapy have symptoms relative to acid reflux, and in such cases, an alternate diagnosis, especially EE, has to be considered.110 Compared with the more potent PPI, H2 provides the advantage of prompt heartburn relief and can be administered as a complement, for example, to improve nocturnal gastric acid control in patients with GERD taking PPI. Sucralfate, which can adhere to gastric mucosa, has esophagitis healing rates comparable to H2RA and is given during pregnancy. Surgery can be considered in young patients with severe disease, implying a long-lasting treatment. Two main techniques exist, consisting in complete fundoplicature (Nissen) and partial fundoplicature (Toupet). The patients have to present with abnormal pHmetry test findings and have to be resistant to PPI.110 Despite surgery, some patients have to continue to take antireflux medication. The most frequent complications are dysphagia (27%), bloating (26%), and excessive gas (47%). Summary Treatment differs between EE and GERD, although a PPI trial treatment is recommended before considering EE. Cases of combined pathology, albeit rare, require both PPI treatment and topical steroids. EVOLUTION (NATURAL HISTORY) Eosinophilic Esophagitis The evaluation of a cohort of 30 adult patients with EE, during a mean 7.2-year follow-up, yielded no evidence of epithelial malignancy or premalignancy. No lymphoproliferative disorder or T-cell clones were found by peripheral blood flow cytometry,111 reinforcing the absence of malignancy in association with EE. Although esophageal eosinophilia persists over time, a significant decrease in both eosinophils and basal cell hyperplasia, as well as papillary elongation, has been found. The major complication of EE is esophageal remodeling and narrowing, although the risk of fibrosis remains to be defined. Gastroesophageal Reflux Peptic strictures and Barrett esophagus, which both represent aberrant forms of esophageal repair, are the 2 main complications of GERD.12 Among the population with reflux symptoms, the rate of complications is very low (1%).4,112 Some authors believe that GERD has no real evolution potential and that, according to one study,112 an adequately performed baseline biopsy with a good evaluation of the gastroesophageal junction is sufficient in patients with no sign of Barrett esophagus. Strictures may develop in cases of severe esophagitis but are well prevented by PPI and tend to become uncommon.12,110 CONCLUSION AND PERSPECTIVES Overlap exists between EE and GERD, especially in clinical presentation and histologic findings. These 2 entities respond to different treatment modalities. Recently, the relationship between EE and GERD has been addressed, with special focus on the association between
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the 2 entities.2,47 Do they in some instances coexist by chance, or does one of the conditions contribute to or cause the other?2,47 Caution is the essence, and a PPI treatment trial, if successful, should not, however, exclude EE, given the possible coexistence of EE and GERD.2,47 In this setting, it is essential to integrate histologic findings in the overall clinical and endoscopic evaluation. Clear-cut features are infrequent, and we have strived to illustrate the 3 main situations that pathologists face in their practices (see Figure 4, A through C). Another word of caution comes from the thorough review by Dellon et al113 of the literature on EE in English. From their analysis of 116 eligible articles published from 1950 to the end of year 2006, the authors113 have identified great variability in the defined cut-off points of esophageal eosinophilic infiltration and in eosinophilic density (eosinophils/mm2) because of different HPF areas per microscope and a frequent lack of diagnostic protocols. The authors113 insist on the need for evidence-based prospective studies, with rigorously defined methodologies and accurately described biopsy protocols. Additional follow-up studies are needed to better delineate EE and GERD notably in the pediatric EE population to better define disease behavior during passage to adulthood and to assess whether pediatric and adult EE represent a continuum. Identification of biologic markers, which allow both diagnostic confirmation and evaluation of disease severity, should also optimize patient care and help reduce the risks and discomfort related to unnecessary endoscopic procedures. New therapeutic modalities will also likely be obtained from new insights in the immunoallergic and genetic pathways involved in these diseases.
We thank J.-M. Dumonceau, MD, who kindly provided the ttimann, for the schematic endoscopic image, and P.-A. Ru illustrations. Author M. Genevay is a Nuovo Soldati fellow, funded by the Foundation pour la recherche Nuovo Soldati Fellowship Fund.
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Arch Pathol Lab MedVol 134, June 2010

Esophagitis With EosinophilsGenevay et al