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Eosinophilic Esophagitis: Clinical Manifestations, Diagnosis, and Management

Ami P. Belmont and Paul George, MD, MHPE

Volume 56 - Issue 5 - May 2016

ABSTRACT: Eosinophilic esophagitis (EoE) is an increasingly prevalent disease in the pediatric and adult populations and is a major cause of gastrointestinal (GI) tract morbidity. EoE is a diagnosis that often is missed, largely related to its nonspecific presentation—GI tract symptoms such as feeding difficulties, vomiting, and abdominal pain in pediatric cases, and refractory heartburn, dysphagia, and food impaction in adult cases. Although it often is confused with gastroesophageal reflux disease, EoE differs in that it does not respond to acid-suppression therapy and is characterized by diffuse esophageal involvement. The pathophysiology is related to a chronic type 2 helper T cell (TH2) antigen-mediated immune response, characterized histologically by inflammation with a prominence of eosinophils and clinically by a high concurrent rate of allergic diatheses. Management includes evaluation by an allergist/immunologist, dietary modification, topical corticosteroids, and follow-up with a gastroenterologist.

KEYWORDS: Eosinophilic esophagitis, gastroesophageal reflux disease, topical corticosteroids

Joey is a 9-year-old boy with a past medical history of eczema and asthma who developed symptoms of abdominal pain, heartburn, and food impaction approximately 4 months ago. His condition has been unresponsive to proton-pump inhibitor (PPI) therapy for the past 2 months. His family medical history is significant for an older brother with eosinophilic esophagitis (EoE).

Manuel is a 65-year-old man with a past medical history of hypertension who presented to the clinic with 4 years of reflux-like symptoms and dysphagia, which has been unresponsive to PPI therapy for the past 4 months. Endoscopy revealed linear furrows in the esophagus and marked inflammation with an eosinophilic predominance.

In both cases, the patients presented with symptoms characteristic of EoE and ultimately received a diagnosis of the condition, which is a major cause of gastrointestinal (GI) tract morbidity and is increasingly being recognized in the adult and pediatric populations. It is important that primary care clinicians and subspecialists are well educated about the disease, the diagnosis of which often is missed, in large part because of its nonspecific presentation.1,2

The disease is characterized clinically by symptoms related to esophageal dysfunction, including dysphagia, heartburn, feeding difficulty, vomiting, abdominal pain, and food impaction.1 While the symptoms are similar to those of gastroesophageal reflux disease (GERD), the pathophysiology of EoE instead is related to chronic antigen-mediated and immunologically mediated inflammation characterized histologically by the prominence of eosinophils, and, critically, the symptoms do not improve with typical antireflux treatment.2,3

This review of EoE outlines the key epidemiologic, clinical, and pathophysiologic characteristics, as well as EoE treatment regimens for both the pediatric and adult populations.

EPIDEMIOLOGY

EoE had not been described explicitly in the literature until 1995, when Kelly and colleagues4 described a group of 10 children with long-term reflux symptoms that failed to improve with antireflux treatment regimens but improved with an elemental diet. The estimated US incidence rate of pediatric EoE is 1 case per 10,000 children per year, with a prevalence rate of 6 to 30 cases per 100,000.1,5

In adults, EoE most commonly presents in young men, typically in the 20- to 30-year-old age range, with symptoms having been present for approximately 4 years.6,7 Notably, reported US prevalence rates have been increasing in the past 2 decades; this increase is thought to be a result of both increased recognition and increased occurrence rates.5,8 In a series of prospective studies examining rates of EoE in patients undergoing endoscopy for upper GI tract complaints, EoE was diagnosed in 6.5% to 12% of patients in these groups, with a relative risk of 9.5 if a patient was younger than 50 years old.9,10 However, because of its nonspecific symptoms, EoE remains underdiagnosed or is diagnosed after substantial delay. One retrospective study showed a median delay in diagnosis of 6 years, with increased complications (such as esophageal strictures) in patients with time.11

Notably, in both children and adults, an estimated 50% to 82% of patients with EoE are also atopic, with concurrent asthma, atopic dermatitis, and/or allergic rhinitis.1,2,10,12,13 In accordance, the pathophysiology is hypothesized to be secondary to a type 2 helper T cell (TH2)-mediated inflammatory response to food and/or environmental allergens.14,15 Studies suggest that there may be regional variation in the United States, with a higher prevalence in Northeastern states, in cold and arid zones, and in urban (vs rural) settings.16,17 The disease also appears to be more common in males and in white children.1,18

PATHOPHYSIOLOGY, GENETIC BASIS OF EoE

As mentioned, EoE is considered an immunologically driven disease in which environmental or food allergens trigger a TH2 inflammatory response. The cytokines released in the inflammatory cascade include interleukins 4, 5, 13, which in turn initiate the release of eotaxin-3, a potent recruiter of eosinophils, into the esophageal mucosa.2,6 Eosinophils produce additional proinflammatory mediators and recruit additional inflammatory cells, including mast cells and fibroblasts. Over time, local tissue damage, esophageal remodeling, and fibrosis results.2,7

Recent literature shows a clear genetic basis for EoE, including familial clustering and, on a molecular level, upregulation of a transcriptome for interleukin 13 (IL-13) and eotaxin-3.19,20 Furthermore, evidence suggests that abnormal gene expression of eotaxin-3 is downregulated by standard-of-care treatment with topical corticosteroids.21 Genome-wide analysis studies have also identified genetic predisposition to EoE located at 5q22 and associated with thymic stromal lymphopoietin (TSLP), which is a cytokine involved in TH2 cell differentiation. In one study, TSLP also was overexpressed in the esophagus of patients with EoE, lending further evidence to its role in disease pathophysiology.22 Other genome-wide studies corroborated these results and also found genetic predisposition at 2p23 spanning CAPN14, which is also upregulated both with disease activity and with exposure to IL-13 through epigenetic modification of its gene locus.23

In summary, it is clear from familial clustering, the known TH2-mediated disease response, and the several genetic defects associated with EoE that genetics play a key role in disease pathophysiology, albeit in a poorly defined interplay with genetic, environmental, and host immune factors. While multiple studies have documented numerous allergens, cytokines, and genes involved in the disease pathophysiology, we have yet to develop targeted diagnostic and treatment tools with these results.

CLINICAL PRESENTATION

Clinically, symptoms vary by age. Feeding dysfunction is predominant in younger children, while vomiting and abdominal pain are principal complaints in school-aged children.24 In contrast, dysphagia and food impaction are the chief symptoms in older children and adolescents.2,25 Evidence suggests progression to dysphagia and food impaction with disease course and aging.19 In a study of children with a mean age of 9 years, the most common presenting complaint was symptoms of GERD (85%) or dysphagia (18%).26 In contrast, in adults the most common symptoms are dysphagia, food impaction, centrally located chest pain, upper abdominal pain, and critically, symptoms of GERD that do not respond to PPIs.2,27-31 Esophageal dysmotility also may be observed, implying involvement of the muscular layers of the esophagus, as well.32,33

The differential diagnosis of EoE is broad. Most notably, it is important to differentiate EoE from GERD, since the health implications of both conditions, barring appropriate treatment, include increased incidence of fibrotic esophageal strictures, and in the case of GERD, Barrett esophagus and esophageal cancer definitively. Nonetheless, distinguishing between GERD and EoE is difficult due to their similar symptoms (heartburn, dysphagia, feeding dysfunction) and that, histologically, eosinophils also are commonly seen in GERD.

The other diagnosis most difficult to distinguish from EoE is PPI-responsive esophageal eosinophilia (PPI-REE), which is a subgroup of EoE that meets criteria for EoE based on histopathology but is responsive PPI treatment. In order to distinguish EoE from PPI-REE, endoscopic biopsy samples must be taken after 2 months of PPI therapy. Less is known about PPI-REE and treatments for this subgroup. Furthermore, it is unclear whether this group has GERD concurrently, has an atypical presentation of GERD, or has a variant of EoE that is PPI-responsive.2,7 Clinical features and pH testing do not predict a response.2,34

The differential diagnosis of EoE also includes infection, parasitic diseases, drug reactions, inflammatory bowel disease, and autoimmune disease, as well as eosinophilic gastroenteritis, hypereosinophilic syndrome (persistent eosinophilia with damage to multiple organs), and connective tissue disease.

DIAGNOSIS

Diagnosis of EoE should encompass a comprehensive understanding of symptomatology and pathologic/histologic features from endoscopic biopsy samples. For this reason, endoscopic biopsy is necessary for diagnosis. Hallmark gross endoscopic features include linear vertical furrowing, scattered white eosinophil-containing exudate, and both fixed rings (“trachealization” or “corrugated rings”) or transient rings (“feline folds” or “felinization”).3,7 However, mucosal abnormalities can be nonspecific, and the esophageal mucosa can appear grossly normal in up to 33% patients.2 In comparison with GERD, EoE also can be distinguished by diffuse involvement of the esophagus, whereas inflammation in GERD is seen more distally.2,5 Notably, patients must be on PPI therapy 2 months in anticipation of the endoscopy.

Optimal pathologic evaluation includes biopsy specimens from multiple areas of the esophagus (including proximal and distal regions), as well as evaluation for the peak eosinophil value (by examining the area with highest density eosinophils), surface layering of eosinophils, eosinophilic microabscesses and extracellular granules (clusters of more than 4 eosinophils), basal cell hyperplasia, and lamina propria fibrosis.2,3 Although not diagnostic, ancillary studies can include radiographic imaging (eg, esophagogram) in select cases to further characterize potential strictures or other anatomic abnormalities.2

Current guidelines outline that EoE is a clinical and pathologic diagnosis defined by symptoms suggestive of esophageal dysfunction and, histopathologically, by eosinophil-predominant inflammation.2,3 Clinically, patients must demonstrate no response to acid suppression (a high-dose PPI for 6 to 8 weeks), while symptoms should improve with dietary eliminations and/or corticosteroids. The diagnosis is dependent on esophageal biopsy tissue consistent with at least 15 eosinophils per high-power field (hpf) and normal mucosa in the stomach and small intestine. In select cases, patients with a suspicious clinical history may be diagnosed with EoE without 15 eosinophils/hpf if other histopathologic evidence is in alignment with eosinophilic inflammation (eg, eosinophilic microabscesses or lamina propria fibrosis). Lastly, other causes of esophageal eosinophilia must also be excluded, including PPI-REE.2,3

In order to distinguish EoE from PPI-REE, American College of Gastroenterology (ACG) guidelines released in 2013 outline that PPI-REE should be diagnosed in symptomatic patients with histologic evidence of eosinophilia that retreats in response to proton-pump inhibition (vs continued diffuse eosinophilia in cases of EoE).3 

The guidelines also note that a clinical, endoscopic, and histologic response to a PPI cannot lead to a diagnosis of GERD without also considering the results of additional standard-of-care evaluation for GERD, such as ambulatory pH testing in select cases.3

MANAGEMENT AND TREATMENT OPTIONS

Treatment of EoE is directed at improving patient symptoms and esophageal histology (monitored with interval endoscopic biopsies), as well as preventing disease complications, including esophageal strictures, esophageal rupture, and food impaction. Management of EoE includes dietary interventions, medications, and routine endoscopy (with intervention if needed).

Upon diagnosis, it is also recommended that patients undergo evaluation by a gastroenterologist and an allergist/immunologist because of the high comorbidity of EoE with allergies and because the results may aid in guiding therapy. Given that allergens are implicated in disease pathogenesis, dietary approaches are an option for first-line therapy.2,35-37 This includes the use of an elemental diet, empiric dietary exclusion (milk, soy, wheat, peanuts, shellfish, etc), and targeted food elimination.2,35,36 However, adherence can be poor to such approaches and necessitates a motivated patient/family, adequate resources, and a cooperative patient. Therefore, the decision to employ a dietary treatment strategy should be tailored to each patient and made in conjunction with a registered dietitian.3 Treatment efficacy should be assessed with follow-up interval endoscopy with biopsy.3

Alternatively, pharmacologic options for EoE include PPIs and oral corticosteroids. Despite that PPIs do not alleviate symptoms, there is some evidence that they decrease eotaxin-3, thus diminishing eosinophilic inflammatory pathways.3 Oral corticosteroids are swallowed in order to topically coat the esophagus (Table) and also reduce inflammatory processes.

In the pediatric population, many sources recommend oral corticosteroids for a 6- to 8-week course given the risk of adverse effects. However, no guideline exists on the optimal duration of treatment after initial treatment in this population.2,7 In general, topical corticosteroids have been well tolerated, and studies have shown no evidence of adrenal suppression with an initial 6- to 8-week course.15 However, more safety data examining long-term use in children (and adults) are necessary. Nonetheless, many experts suggest ongoing therapy as esophageal eosinophilia and symptoms generally return after the discontinuation of therapy. Therefore, these experts recommend continuing nutritional therapy and topical glucocorticoids in frequency and doses in an attempt to help patients remain asymptomatic.2,7

In contrast, in the adult population, ACG guidelines outright recommend maintenance fluticasone or oral viscous budesonide.3 In the event of severe symptoms, such as debilitating dysphagia, weight loss, or hospitalization, systemic corticosteroids can be considered.2

In more severe cases where patients develop esophageal strictures despite therapy, endoscopic esophageal dilatation may be considered. However, patients should be warned in the initial consultation of possible adverse effects associated this intervention, including postprocedural chest pain, bleeding, and esophageal perforation.3

Notably, limitations in current treatment strategies include inconsistent correlations between symptomatic response and esophageal histologic response as demonstrated in multiple studies, as well as variable primary outcomes in treatment trials.3,38-40 Further research also is needed to continue evaluating targeted treatment modalities and biologic agents.3

LONG-TERM IMPLICATIONS

Studies examining disease course and long-term sequelae of EoE in the pediatric and adult populations are limited. Nonetheless, at present, known complications typically seen in adults include food impaction, stricture formation, and spontaneous or endoscopic esophageal perforation.2 Because EoE is a chronic disease characterized by long-term inflammation, patients’ cases should be followed regularly by a gastroenterologist, with periodic endoscopy to evaluate for disease progression.

Ami P. Belmont is a graduating medical student at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. She is starting an internal medicine and pediatrics residency at Yale University in New Haven, Connecticut.

Paul George, MD, MHPE, is director of curriculum for the Primary Care-Population Medicine Program, an assistant professor of family medicine at the Warren Alpert Medical School of Brown University.

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