Eosinophilic Disorders of the Gastrointestinal Tract

Eosinophil Biology and Potential Diagnostic and Therapeutic Targets

Eosinophils contain a full complement of mediators (cytokines and chemokines) necessary to regulate both innate and adaptive immune responses. They can function as antigen-presenting cells, and they express Th2 cytokines (IL-4, IL-5, IL-13), Th1 cytokines (interferon-γ), proinflammatory cytokines (TNF, IL-6, and IL-8), and inhibitory cytokines (transforming growth factor [TGF]-β and IL-10), as well as receptors for many of these cytokines. Eosinophils are produced in the bone marrow from pluripotent stem cells under the regulation of the transcription factor globin transcription factor 1 ¹⁶ the cytokines IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor. Eosinophils contain specialized secondary granules whose protein content is toxic to a variety of tissues, including intestinal epithelium. Eosinophil granules contain a crystalloid core composed of major basic protein (MBP)-1 and MBP-2 and a matrix composed of eosinophil cationic protein (ECP), eosinophil-derived neurotoxin, and eosinophil peroxidase. Clinical investigations have demonstrated extracellular deposition of MBP and ECP in the small bowel of patients with eosinophilic gastroenteritis. Circulating levels of eosinophil-derived neurotoxin are also elevated in patients with EoE and can distinguish patients with active and inactive disease.

IL-5 is the most specific to the eosinophil lineage and is responsible for the selective differentiation of eosinophils, their release from the bone marrow into the peripheral circulation, and their survival. Studies in mice have implicated that the level of IL-5 expression positively correlates with blood eosinophilia, with reduced IL-5 levels causing a marked reduction of eosinophils in the blood, lungs, and GI tract after allergen challenge. These results have led to development of IL-5 modulators such as reslizumab and mepolizumab. Reslizumab, a neutralizing antibody against IL-5, significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with EoE in a double-blind, randomized, placebo-controlled trial. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts. These two anti–IL-5 drugs, as well as an eosinophil-depleting monoclonal antibody directed against the IL-5 receptor, are now FDA approved for eosinophilic asthma and are likely to have additional applications. These results also may suggest the importance of other molecules involved in the tissue eosinophil-related inflammatory changes that are characteristic of EoE pathogenesis. Indeed, other products of Th2 cells (e.g., IL-4, IL-13) can affect eosinophils. IL-4 and IL-13 induce indirect eosinophil recruitment and survival via several cooperative mechanisms. They mediate their function by inducing endothelial expression of critical adhesion molecules that bind to the β1 and β2 integrins on eosinophils (e.g., intercellular adhesion molecule-1, vascular cell adhesion molecule-1), as well as of eosinophil active chemokines (e.g., eotaxins) and other molecules that influence eosinophils (e.g., chitinases). IL-4 and IL-13 signal through a common receptor subunit IL-4Rα that utilizes the Janus kinase/signal transducer and activator of transcription (STAT)-6 pathway and eosinophils express the predominant IL-4 receptor composed of IL-4Rα and the common gamma chain. Mice with targeted deletion of Stat6 have impaired development of Th2-associated responses in the GI tract. In addition, activated STAT-6 dimers bind to specific promoter motifs located in a series of inflammatory genes, such as the eotaxin-1, eotaxin-2, and eotaxin-3 promoters. Indeed, IL-13 was found in several studies to have a positive correlation with disease activity in esophageal tissue and with IL5 and eotaxin-3 messenger RNA expression. In addition, IL-13 overexpression in mice induces EoE-like changes, including an esophageal transcriptome that partly overlaps with the EoE transcriptome. Early clinical trials with anti-IL-13, as well as anti-IL-4 receptor antibodies, have demonstrated reduction in esophageal eosinophilia and improvement of histology, endoscopic, and clinical symptoms; further studies will hopefully establish the positioning of these mechanism-based therapies for EoE and likely other EGIDs. Eosinophil localization to the lamina propria in the GI tract is regulated by eotaxins, chemokines constitutively expressed throughout the GI tract. The eotaxin receptor, chemokine (C-C motif) receptor (CCR)-3, is primarily expressed on eosinophils. Among the 3 eotaxins, eotaxin-3 has been shown to have the strongest correlation with EoE pathogenesis. Analysis of 288 esophageal biopsies revealed that eotaxin-3 messenger RNA level alone had 89% sensitivity for distinguishing individuals with and without EoE. Collectively, these studies suggest that IL-5, IL-13, and eotaxin-3 can potentially serve as surrogate markers for diagnosis and disease activity. In addition, these studies have provided the impetus for the development of therapeutic agents aimed at blocking the action of eotaxins and/or CCR3. Indeed, small-molecule inhibitors of CCR3 and a humanized anti–human eotaxin-1 antibody have been developed. Results with a phase I trial of humanized anti-eotaxin-1 in patients with allergic rhinitis have shown no serious adverse responses when this drug is administered by intravenous or intranasal routes. Notably, anti-eotaxin-1 lowers levels of eosinophils in nasal washes and nasal biopsies and improves nasal patency. Anti-eotaxin-1 may be particularly helpful for patients with eosinophil-dominant asthma and/or severe asthma in which eotaxin-1 is preferentially increased but this has not yet been tested clinically. In addition, anti-eotaxin-1 may have a benefit in other GI disorders characterized by eosinophilia such as IBD. However, important lessons from the anti-IL-5 antibody clinical trials suggest that researchers should focus on both histologic and clinical end points and target patients with higher eosinophil and eotaxin-1 levels.

The EoE diagnostic panel (EDP) has been introduced more recently ( Table 30.1 ). The EDP is a set of 96 genes discretely expressed in the esophagus of EoE patients, with a 96% sensitivity and 98% specificity in pinpointing EoE in adult and pediatric patients, in addition to identifying those patients with swallowed glucocorticoid exposure. The EDP is also helpful as a predictive tool in patients with subclinical histology (<15 eosinophils/high-power field [HPF]).

Gastrointestinal Eosinophils in Healthy States

Eosinophils have been noted to be present at low levels in numerous tissues and at substantial levels in the GI tract, spleen, lymph nodes, thymus, and adipose tissue in healthy states. Interestingly, eosinophil infiltration was associated with eosinophil degranulation only in the GI tract; however, it was previously suggested that morphologic degranulation may be normally observed in the GI tract and perhaps related to tissue processing. In the healthy pediatric GI tract, eosinophil levels progressively increase from the proximal to the distal intestine, with the esophagus normally being devoid of eosinophils ( Table 30.2 lists the level of eosinophils in the GI tract of apparently normal endoscopic biopsies). In the GI tract of conventional healthy mice (i.e., untreated, wild-type mice maintained under pathogen-free conditions), eosinophils are normally present in the lamina propria of the stomach, small intestine, cecum, and colon and are not normally present in Peyer’s patches or intraepithelial locations, although they commonly infiltrate these regions in murine models of EGIDs. Interestingly, fetal mice have eosinophils located in similar regions and in similar concentrations to adult mice, providing evidence that eosinophil homing into the GI tract occurs independent of endogenous flora. Tissue-dwelling eosinophils have distinct cytokine expression patterns under inflammatory or noninflammatory conditions, with esophageal eosinophils from patients with EoE expressing relatively high levels of Th2 cytokines.

Eosinophil-Associated Gastrointestinal Disorders

Eosinophil accumulation in the GI tract is a common feature of numerous GI disorders, including classic IgE-mediated food allergy, eosinophilic gastroenteritis, allergic colitis, EoE, IBD, , and GERD ( Table 30.3 ). In IBD, eosinophils usually represent only a small percentage of the infiltrating leukocytes, but their level has been proposed to be a negative prognostic indicator. Similarly, in GERD, there are typically only low levels of esophageal eosinophils, but the entity of PPI-responsive esophageal eosinophilia (PPI-REE) has been described. PPI-REE has overlapping endoscopic, genetic, and histologic features with EoE and is now considered part of the same disease spectrum. EGIDs (i.e., EoE, EG, eosinophilic enteritis, and EC) are defined as disorders that primarily affect the GI tract with eosinophil-rich inflammation in the absence of known causes for eosinophilia (e.g., drug reactions, parasitic infections, malignancy). In addition, EoE and inherited connective tissue disorders (CTD) share excessive production of TGF-β; EoE increases the risk for CTD by 8-fold. This association is particularly observed in hypermobility syndromes like Loeys-Dietz syndrome, Marfan syndrome type II, and Ehlers-Danlos syndrome; this is referred to as EoE-CTD. Patients with EGIDs suffer from a variety of problems, including failure to thrive, abdominal pain, irritability, gastric dysmotility, vomiting, diarrhea, and dysphagia.

Evidence is accumulating that supports the concept that EGIDs arise secondarily to the interplay of genetic and environmental factors. Notably, a large percentage (∼10%) of patients suffering from EGIDs, especially EoE, have an immediate family member with EGIDs. In addition, several lines of evidence support an allergic etiology, including the findings of mast cell degranulation in tissue specimens, that approximately 75% of patients with EGIDs are atopic, that disease severity can typically be reversed by institution of an allergen-free diet, and, importantly, that the disease often relapses upon food reintroduction. In addition, murine models of EGIDs support a potential allergic etiology for these disorders. Interestingly, despite the common finding of food-specific IgE in patients with EGIDs, food-induced anaphylactic responses occur in only a minority of patients. Thus, EGIDs have properties that fall between pure IgE-mediated food allergy and cellular-mediated hypersensitivity disorders (e.g., celiac disease).

Although the incidence of primary EGIDs has not been rigorously calculated, a mini-epidemic of these diseases (especially EoE) has been noted over the past decade. For example, EoE is a global health problem now reported in Australia, Brazil, England, Italy, Israel, Japan, Spain, and Switzerland. Liacouras and his group at Children’s Hospital of Philadelphia have found that approximately 10% of their pediatric patients with GERD-like symptoms who are unresponsive to acid blockade have EoE. Furuta and his colleagues at Boston Children’s Hospital have reported that 6% of their patients with esophagitis have EoE. Finally, Noel et al. have reported a prevalence of approximately 1:1000 children in the Cincinnati metropolitan area over a 10-year period. With the introduction of ICD-9/10-CM codes for these conditions, recent investigations by Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators were able to accurately estimate the prevalence of EGIDs. Using a highly specific case definition, the prevalence of EoE has been estimated to be between 39.0 and 56.7/100,000 in the US, consistent with earlier work, with an extrapolated national prevalence of approximately 105,000 to 150,000 cases. Despite increases in EoE prevalence over the past 2 decades, however, it is still a rare disease. A recent meta-analysis estimated the pooled prevalence of just 22.7/100,000, suggesting that even fewer than 100,000 cases exist in the US. In a separate study done by CEGIR, the prevalence of EG was found to be 6.4/100,000, extrapolated to approximately 17,000 cases in the US, and the prevalence of EC was estimated at 3.5/100,000, extrapolated to approximately 9000 cases ; this rare prevalence was confirmed in an independent study as well.

EGIDs typically occur independent of peripheral blood eosinophilia (>50% of the time), indicating the potential significance of GI-specific mechanisms for regulating eosinophil levels; indeed, the importance of the eotaxin pathway in this process has been demonstrated. However, some patients with EGIDs (typically those with EG) can have substantially elevated levels of peripheral blood eosinophils and meet the diagnostic criteria for hypereosinophilic syndrome (HES) ; this syndrome is defined by sustained, severe peripheral blood eosinophilia (>1500 cells/mm ³ ) and the presence of end organ involvement in the absence of known causes for eosinophilia. Notably, while HES commonly involves the GI tract, the other end organs typically associated with HES such as the heart and skin are uncommonly involved in EGIDs. It has been appreciated that a subset of patients with HES have a microdeletion on chromosome 4 that generates an activated tyrosine kinase (FIP1L1-PDGFRA fusion gene) susceptible to imatinib mesylate therapy ; the possible occurrence of this and other genetic events in patients with EGIDs, especially those with significant circulating eosinophilia, is currently being investigated.

Eosinophilic Esophagitis

As the esophagus is normally devoid of eosinophils, finding esophageal eosinophils denotes pathology. It is now appreciated that many disorders are accompanied by eosinophil infiltration in the esophagus, such as EoE, eosinophilic gastroenteritis, GERD, parasitic and fungal infections, IBD, HES, esophageal leiomyomatosis, myeloproliferative disorders, carcinomatosis, polyarteritis nodosa, allergic vasculitis, collagen vascular diseases such as scleroderma, pemphigus vegetans, and drug injury. Eosinophil-associated esophageal disorders are classified into primary and secondary. The primary subtype is referred to as EoE and includes the atopic, nonatopic, and syndromic disorders, particularly those associated with inherited CTD such as hypermobility syndrome, and familial EoE variants. The familial form of EoE is seen in 5% to 10% of patients, and the sibling recurrence risk ratio has been estimated to be over 50-fold. Moreover, there are several other mendelian diseases associated with EoE: ERBIN deficiency, Netherton syndrome, PTEN hamartoma tumor syndrome, and severe atopy syndrome associated with metabolic wasting syndrome (see Table 30.3 ). The secondary subtype is divided into 2 groups, one composed of systemic eosinophilic disorders (i.e., HES) and the other of essentially noneosinophilic disorders.

Etiology

EoE is a clinicopathologic condition that is commonly recognized among both pediatric and adult patients presenting to allergy and gastroenterology clinics throughout the world. The annual EoE incidence rates varying between 0.1 and 1.2 per 10,000 in several studies, with EoE representing the second most common cause of chronic esophagitis. The etiology of EoE is poorly understood, but food allergy has been implicated as a primary contributor. In fact, the majority of patients have evidence of a food allergen and aeroallergen sensitization as defined by skin prick and/or allergen-specific IgE tests; however, only a minority have a history of food anaphylaxis. Although considered a food allergen driven allergic disease, evidence has accumulated that the positive skin tests and allergen-specific IgE are markers of the involved immunologic response rather than reflective of the primary mechanism. It has also been suggested that esophageal eosinophilic inflammation is mechanistically linked with pulmonary inflammation. This latter theory is based on the finding that repeated delivery of specific allergens or the Th2 cytokine IL-13 to the lung of mice, as well transgenic overexpression of IL-13 in the lung of mice, induces experimental EoE and the observation of increased eosinophil accumulation in the esophagus of patients with seasonal allergic rhinitis with hypersensitivity to grass. Other studies have also indicated a strong relationship between atopy and EoE. Indeed, patients with EoE commonly report seasonal variations in their esophageal symptoms. In addition to eosinophils, T cells and mast cells are elevated in esophageal mucosal biopsies, suggesting chronic Th2-associated inflammation. Elevated TGF-β, produced by eosinophils and mast cells, has been shown to contribute to tissue remodeling and smooth muscle dysfunction. Furthermore, epicutaneous antigen exposure primes the esophagus for marked eosinophilic inflammation following a single airway antigen challenge.

The genome-wide microarray expression profile analysis of esophageal tissue was a landmark advance in EoE research. Investigators compared gene transcript expression in the esophageal tissue of patients with EoE or chronic esophagitis (typical of GERD) and normal individuals. Notably, the dysregulated expression of approximately 1% of the entire human genome constituted an EoE genetic signature. Interestingly, eotaxin-3 was the most overexpressed gene in patients with EoE, and levels correlated with disease severity; in fact, overexpression of eotaxin-3 alone has a predictive value of 89% in diagnosing EoE from a single esophageal biopsy. The same investigators demonstrated that mice with a genetic ablation of the eotaxin receptor (CCR3) were protected from the development of experimental EoE. Collectively, these results strongly implicate eotaxin-3 in the pathoetiology of EoE and offer a molecular connection between Th2 inflammation and the development of EoE. The first genome-wide association study linked EoE to the genetic locus region 5q22, which harbors the TSLP gene; notably, TSLP has a known role in processes germane to EoE, including polarization of Th2 immunity and induction of eotaxins. Subsequent genome wide association studies validated the TSLP locus and also identified a strong genetic susceptibility locus at 2p23, at the CAPN14 gene locus. CAPN14 encodes for calpain-14, an esophageal-specific intracellular cysteine protease that regulates epithelial cell barrier function. Interestingly, calpain-14 is induced by IL-13, linking allergic type 2 adaptive immune responses with an innate epithelial cell response. As such, this esophageal specific pathway helps to explain why allergic individuals develop EoE, linking type 2 immunity (allergic) with esophageal specific responses. In support of this, genetic interplay (epistasis) of CAPN14 genetic variants with atopy susceptibility variants have been demonstrated. In addition, using a broad candidate-gene approach, genetic variants in TSLP and its receptor have been associated with EoE susceptibility.

Clinical Features and Diagnostic Studies

EoE represents a chronic, antigen-driven, immune-mediated mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE should be diagnosed by clinicians, taking into consideration all clinical and pathologic information; neither of these parameters should be interpreted in isolation. The diagnostic criteria for EoE in 2011, emphasized that EoE requires finding 15 or more eosinophils/HPF (peak value) in the esophagus. This definition is based on a 2017 consensus recommendation that PPI-responsiveness is not considered in the diagnosis of EoE, as PPI-REE has phenotypic, genetic, and molecular features that overlap with PPI-resistant esophageal eosinophilia. With few exceptions, 15 eosinophils/HPF (peak value) is considered a minimum threshold for a diagnosis of EoE. The consequences of this eosinophil-predominant inflammation of the esophagus can have a profound systemic and emotional impact for patients and their families.

In regard to the history of EoE, this disorder has been identified in the pediatric and adult patient populations, typically in male patients with evidence of atopy, and the disease most often responds to either topical glucocorticoid therapies or dietary restrictions. At this time, therapy for EoE is chronic, with recurrence of disease activity being noted rapidly after cessation of either dietary or drug-based therapies. The primary symptoms of this disorder vary with the age of the patient. These symptoms include difficulties with eating, failure to thrive, chest and/or abdominal pain, dysphagia, and food impaction. These symptoms generally occur in chronological order depending upon patient age, providing supportive evidence that the natural history of pediatric EoE progresses into adult EoE. Infants and toddlers often present with feeding difficulties, whereas school-aged children are more likely to present with vomiting or pain. Dysphagia is a predominant symptom in adolescents. EoE in children is most often present in association with other manifestations of atopic diathesis (food allergy, asthma, eczema, chronic rhinitis, and environmental allergies) that also follows chronologic order in a similar fashion to the “allergic (or ‘atopic’) march.” Symptoms in adult patients with EoE are somewhat stereotypical and include dysphagia, non—swallowing-associated chest pain, food impaction, and upper abdominal pain. Solid-food dysphagia continues to be the most common presenting symptom. Food impaction necessitating endoscopic bolus removal occurs in 33% to 54% of adults with EoE.

The assessment of EoE includes an allergy evaluation to look for coexisting allergic diseases, given the association of EoE with the atopic march. It is no longer considered necessary to look for food allergen and aeroallergen sensitization either by skin prick tests or measurement of allergen-specific IgE in serum, as this has little bearing on successful diet therapy compared with empiric avoidance of the most common allergens. However, these tests may be useful when deciding which foods to add back to the diet, especially when EoE patients have a history of acute reactions to food (anaphylaxis). Exclusion of GERD as the primary cause of esophageal eosinophilia should be considered when clinically appropriate. A study has suggested that evaluation of food protein sensitization by delayed skin patch testing increases the identification of food allergy compared with skin prick testing alone, but these findings have been primarily limited to one site and are not generally recommended.

Physical examinations for patients with EoE are useful to identify normal growth patterns in children and to identify comorbid allergic diseases in both children and adults; however, no features on physical examination are specific in making the diagnosis of EoE. In addition, no oral or pharyngeal manifestations of EoE have been identified, although some children who have EoE might present with laryngeal symptoms. Esophageal abnormalities identifiable by means of endoscopy in patients with EoE include fixed esophageal rings/trachealization (a.k.a. fibrostenotic complications), transient esophageal rings, whitish exudates, longitudinal furrows ( Fig. 30.1 showing furrowing and exudates), edema, diffuse esophageal narrowing, narrow-caliber esophagus, and esophageal lacerations induced by passage of the endoscope (a manifestation of mucosal fragility that, when severe, gives the esophagus the appearance of crepe paper). However, because all of these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for EoE. Clinical guidelines from the ACG in 2013 suggest that evaluating gastroenterologists can use the EoE Endoscopic Reference Score to classify and grade EoE, this system is described in Table 30.4 . Furthermore, the accuracy of the Endoscopic Reference Score has been evaluated and the classification system can successfully identify patients with EoE and can also be used to evaluate response to treatment. Endoscopy with esophageal mucosal biopsy remains the only reliable diagnostic test for EoE ( Fig. 30.2 ). Typical histologic findings include presence of 15 or more eosinophils/HPF, dilated intercellular spaces and in some cases also elongated papillae, and inflammation and fibrosis in the lamina propria (see Fig. 30.2 ). In 2017 a newly developed histologic scoring system (HSS) for EoE was validated. In addition to identifying 15 or more eosinophils/HPF, 8 other histologic features were shown to differentiate treated from untreated patients and that the HSS outperforms esophageal eosinophil levels for disease diagnosis and monitoring. The 8 HSS features include eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Severity and extent are scored using a 4-point scale, with 0 being normal and 3 denoting maximum change. However, the finding of isolated esophageal eosinophilia without determining corroborating symptoms and ruling out other causes of esophageal eosinophilia is inadequate to make the diagnosis of EoE. Specifically, some of these presenting symptoms cannot easily distinguish EoE from GERD. The distinguishing features between GERD and EoE are summarized in Table 30.5 . The number and location of eosinophils are helpful when trying to differentiate EoE from GERD. Up to 7 eosinophils/HPF (400×) is most indicative of GERD, 7 to 15 eosinophils/HPF likely represents a combination of GERD and food allergy, and at least 15 eosinophils/HPF is characteristic of EoE. The anatomic location of eosinophils to both the proximal and distal esophagus denotes EoE, while the accumulation of eosinophils mainly in the distal esophagus is characteristic of GERD. Some studies have also identified that mast cells are increased in biopsy specimens from patients with EoE compared with those from patients with GERD. IgE-bearing cells are more common in biopsy specimens from patients with EoE compared with those from patients with GERD and are also not detected in control specimens. Esophageal pH monitoring (and pH impedance, where available) is a useful diagnostic test to evaluate for GERD in patients with esophageal eosinophilia. In addition, consensus guidelines indicated that barium contrast radiography can identify a number of the anatomic and mucosal abnormalities of EoE but that the sensitivity of radiography as a diagnostic test for this condition appears to be low. Therefore, radiology is not recommended as a routine diagnostic test for EoE but can be helpful in select cases to characterize anatomic abnormalities that can be difficult to define endoscopically and to gather more information regarding the length and diameter of complicated esophageal strictures. A newer technique using the endoluminal functional lumen imaging probe (EndoFLIP) offers a unique evaluation of esophageal function as it relates to EoE. It has been shown that esophageal distensibility is reduced in EoE with an associated risk of food impaction or need for therapeutic dilation. One study even demonstrated improvement in esophageal body distensibility with medical and diet therapies without dilation; this improved distensibility correlated with symptomatic improvement more than the reduction in esophageal mucosal eosinophil count. More studies will need to be completed before EndoFLIP can be used definitively as an outcome measure.

TABLE 30.4

Endoscopic Eosinophilic Esophagitis Reference Score

Adapted from Hirano I, Moy N, Heckamn MG, et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis validation of a novel classification and grading system. Gut 2013;62:489–95.

Major Features

Edema (Also referred to as decreased vascular markings, mucosal pallor)

Grade 0: Absent. Distinct vascularity present

Grade 1: Loss of clarity or absence of vascular markings

Fixed rings (Also referred to concentric rings, corrugated esophagus, corrugated rings, ringed esophagus, trachealization)

Grade 0: None

Grade 1: Mild-subtle circumferential ridges

Grade 2: Moderate-distinct rings that do not impair passage of a standard diagnostic adult endoscope (outer diameter 8-9.5 mm)

Grade 3: Severe-distinct rings that do not permit passage of a diagnostic endoscope

Exudates (Also referred to as white spots, plaques)

Grade 0: None

Grade 1: Mild-lesions involving less than 10% of the esophageal surface area

Grade 2: Severe-lesions involving greater than 10% of the esophageal surface area

Furrows (Also referred to as vertical lines, longitudinal furrows)

Grade 0: Absent

Grade 1: Vertical lines present

Stricture

Grade 0: Absent

Grade 1: Present (specify estimated luminal diameter)

Minor features

Crepe paper esophagus (Mucosal fragility or laceration upon passage of diagnostic endoscope but not after esophageal dilation)

Grade 0: Absent

Grade 1: Present

Narrow-caliber esophagus (Reduced luminal diameter of the majority of the tubular esophagus)

Grade 0: Absent

Grade 1: Present

TABLE 30.5

Comparison of Eosinophilic Esophagitis and GERD

Modified from Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004; 113:11–8. © 2004, with permission from the American Academy of Allergy, Asthma, and Immunology.

Characteristic features	Eosinophilic esophagitis	GERD
Clinical
Prevalence	∼1:1000	∼1:10
Prevalence of atopy	Very high	Normal
Prevalence of food sensitization	Very high	Normal
Gender preference	Male	None
Abdominal pain and vomiting	Common	Common
Food impaction	Common	Uncommon
Investigative Findings
pH probe/impedance study	Normal	Abnormal
Endoscopic furrowing	Very common	Occasional
Histopathology/Pathogenesis
Involvement of proximal esophagus	Yes	No
Involvement of distal esophagus	Yes	Yes
Epithelial hyperplasia	Severely increased	Increased
Eosinophil levels in mucosa	>15/HPF	0-7/HPF
Elevated eotaxin-3 level	Yes	No
EoE diagnostic panel positive	Yes	No
Treatment
H 2 receptor antihistamines	Not helpful	Helpful
Proton pump inhibitors	Helpful in subset	Helpful
Glucocorticoids	Helpful	Not helpful
Specific food antigen elimination	Helpful	Not helpful
Elemental diet	Helpful	Not helpful
Anti–IL-13 and anti–IL-4Rα	Helpful	Not helpful

HPF , High-power field; IL , interleukin.

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