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school of Medicine, University of Colorado Denver, Denver, CO, UsA (D atkins). Department of Pediatrics, section of Pediatric Gastroenterology, Hepatology and Nutrition (r Kramer, gt Furuta), Department of Pathology (K Capocelli, M lovell), The Children’s Hospital Denver, Aurora, CO, UsA.
Correspondence: GT Furuta, The Children’s Hospital, 13123 east 16th Avenue B290, Aurora, CO 80045, UsA furuta.glenn@ tchden.org
eosinophilic esophagitis: the newest esophageal inflammatory diseaseDan Atkins, Robert Kramer, Kelley Capocelli, Mark Lovell and Glenn T. Furuta
abstract | eosinophilic esophagitis (eoe) is a chronic esophageal inflammatory disease of undetermined pathophysiology that results in dense mucosal eosinophilia and esophageal dysfunction. in childhood, vague symptoms associated with GerD and feeding difficulties are the first manifestations of eoe. Adults typically present with dysphagia and food impaction. No pathognomonic features have been identified for eoe and, therefore, its diagnosis must be made on both clinical and histological grounds. effective treatments rely on steroids and dietary exclusions.
Atkins, D. et al. Nat. Rev. Gastroenterol. Hepatol. 6, 267–278 (2009); doi:10.1038/nrgastro.2009.45
Introduction over the past decade, esophageal eosinophilia has been increasingly recognized in children and adults who have symptoms similar to those observed in GerD.1 However, in contrast to patients with GerD, symptoms and histo-pathology are unresponsive to high-dose acid suppression therapy or surgical fundoplication.1 this constellation of findings is consistent with the diagnostic features of a newly-emerged disease termed eosinophilic esopha-gitis (eoe).1 evidence points to eoe as an inflammatory disease of the esophagus that is triggered by an antigen with resultant dense mucosal eosinophilia and esopha-geal dysfunction. this review will focus on clinical and pathological features and allergic manifestations of eoe and will summarize effective treatments for the disease.
Esophageal eosinophilia the definition of esophageal eosinophilia and its inter-pretation continues to change. originally associated with GerD, dense eosinophilic esophageal inflammation is now often reflexively attributed to eoe. as clinicians now pay increased attention to this histological finding, it is important to remember that eosinophilic inflammation may also be associated with other diseases, such as Crohn’s disease and celiac disease.2–12 eosinophilic inflamma-tion must be interpreted within the clinical context in which the biopsy was obtained in order to determine its underlying cause.1
Eosinophilic esophagitis Definition eoe is a disease characterized by a variety of upper gastro-intestinal symptoms that occur in association with dense
esophageal eosinophilia (Box 1); its symptoms and histo-pathology are unresponsive to pharmacological and surgi-cal GerD treatments.1 alternative etiologies responsible for the eosinophilia must be ruled out before eoe can be diagnosed.1,13 eoe has been reported in all age-groups and in all continents except africa.14,15 the prevalence of the disease is not certain, but is estimated to be 1–4 cases per 10,000 individuals.16,17
the natural history of the disease is as yet unknown;18 two case reports suggest an association with Barrett esophagus, but this link has not been verified by other studies.19–21 a number of names and acronyms have been used to describe this relatively new disease, including eosinophilic esophagitis, primary eosinophilic esopha gitis, allergic eosinophilic esophagitis, idiopathic eosinophilic esophagitis and eosinophilic esophagitis (eoe or ee). the acronym ee has become deeply embedded in the allergy literature, but because of increasing confusion with erosive esophagitis (ee) within the gastro enterology community, the acronym eoe will be used in this review.
pathogenesis mechanisms of esophageal eosinophilic inflammation associated with eoe have been investigated in basic and translational studies. mishra et al. conducted a series of studies using murine models of esophageal eosinophilia in which allergens or cytokines were used to initiate esopha-geal eosinophilia.22–25 Aspergillus fumigatus, an ubiqui-tous airborne allergen, was used to sensitize mice, which developed epithelial eosinophilia that was isolated to the esophageal mucosa. Further studies using this model demonstrated that the eosinophilia and colla gen deposi-tion were interleukin 5 (il-5)-dependent.26 translational studies have characterized the inflammatory profile of the mucosa revealing increased CD8+ lymphocytes, proinflammatory cytokines, the immunoglobulin e (ige) receptor, mast cell infiltration, eosinophil degranula tion and, in some cases, basophilia.27–37
Competing interestsG. T. Furuta has declared an association with the following company: Meritage Pharmaceuticals. see the article online for full details of the relationship. The other authors declared no competing interests.
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in a landmark study, Blanchard et al. discovered an eoe transcriptome.38 in this study, a genome-wide microarray analysis was performed on esophageal biopsies obtained from 13 children with eoe compared with five children with chronic esophagitis and six healthy controls. the most upregulated gene product was eotaxin-3 (also known as CCl26), a chemokine critical for eosinophil migration; a single-nucleotide polymorphism in this gene was associated with disease susceptibility. in a series of murine studies, mice deficient in the chemokine recep-tor CCr3 were shown to be protected from eoe. other studies have shown increased expression of the gene encoding eotaxin-3 (CCl26) in the mucosa of animals with eoe.39–42 together, these findings support a role for eotaxin-3 (CCl26) in the pathogenesis of eoe.
the role of acid reflux in the pathogenesis of eoe is a matter of debate. while sant’anna et al. showed that pH monitoring of the distal esophagus revealed increased periods of alkalinization in children with eoe compared with that of healthy controls, rosen et al. demonstrated
Key points
eosinophilic esophagitis is a clinicopathological disease characterized by a ■wide variety of GerD-like symptoms, dysphagia and vomiting that occur in conjunction with dense esophageal eosinophilia
esophageal eosinophilia is a common finding associated with GerD, ■eosinophilic esophagitis, iBD, hypereosinophilic syndrome and celiac disease
No pathognomonic findings in the patient’s history, or laboratory, endoscopic, ■or histological results define eosinophilic esophagitis
effective treatments for eosinophilic esophagitis include corticosteroids and ■dietary exclusions
that acid and nonacid reflux was not increased in chil-dren with eoe using pH-multichannel intraluminal impedance tracings.43,44 the coming years will also bring new enlightenment as to the relationships between GerD and eoe.45 there is probably clinical crossover between these two diseases in some patients that will likely be explained as the esophageal microenvironment becomes better defined.4,9,46
Association with allergic disease several lines of evidence support a role for allergic inflammation in the pathogenesis of eoe. the most obvious evidence for such involvement is the central role of the eosinophil. this cell is often considered synony-mous with allergic disease because of its accumulation in sputum in asthma, in nasal secretions in allergic rhini-tis and in the skin during flares of acute eczema.47 the majority of patients with eoe have comorbid allergic disease such as food allergy, eczema, allergic rhinitis, or asthma accompanied by ige-mediated sensitization to food and/or inhalant allergens.1 an age-related inverse gradient for the presence of coexisiting allergic disease has previously been described in eoe; its frequency is highest in pediatric cohorts, where estimates reach 80%, and lowest in adult cohorts where estimates range from 40% to 70%.1,48 two studies have demonstrated a potential role for airborne allergens in eoe.49,50 Histories of allergic disease in family members are noted in the majority of patients with eoe as exemplified by a report in which 73.5% of 103 patients with eoe had a positive family history of allergic disease.16 the presence of other atopic diseases in patients with eoe affects peripheral eosinophil counts and total ige levels making it diffi-cult to ascribe changes in these parameters specifically to eoe.
as could be predicted by the intimate interaction between foods and the esophageal mucosa, food allergy often accompanies eoe and is considered contributory in a substantial proportion of patients.51 Pediatric studies report coexistent food allergy in up to 73% of patients, whereas adult studies document food allergy in a more widely ranging proportion (25–82%) of patients.49,52 Foods most often implicated in eoe-associated allergies include milk, egg, wheat, soy, peanuts, beans, rye and beef, although a variety of other foods may have a role in individual patients.1 allergic sensitization to more than one food is common in patients with eoe. when large panels of food allergy skin tests were applied to a cohort of 786 patients with eoe from aggregated case series data, the mean number of food allergies identified per patient varied from 2.7 ± 3.3 to 6 ± 4.2.1 in addition to sensitivity to food allergens, sensitivity to seasonal pollen allergens is common in patients with eoe.1 isolated case reports have documented a correlation between pollen allergy skin test results and seasonal changes in eoe symptoms and esophageal eosinophil levels.53,54
allergic reactions to foods are categorized as ige-mediated, non-ige-mediated or combined reactions
Box 1 | Diagnostic features of eosinophilic esophagitis
pediatric features
GerD-like upper gastrointestinal symptoms unresponsive to pharmacological or surgical management, abdominal pain, vomiting, feeding difficulties
adult features
GerD-like upper gastrointestinal symptoms unresponsive to pharmacological or surgical management, dysphagia, food impaction, chest pain
histopathological features
Dense epithelial eosinophilia of the esophageal mucosa (≥15 eosinophils/high power field), normal gastric and duodenal mucosa, eosinophil microabscesses, superficial layering, rete peg elongation, basal zone hyperplasia
radiographic features
esophageal stricture (especially proximal), long-segment esophageal narrowing, esophageal rings
endoscopic features
Linear furrows, concentric rings, schatzki ring, linear shearing and/or splitting, crepe paper esophagus, white exudates
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according to the immune mechanism involved. in ige-mediated food allergy, exposure of a genetically pre-disposed individual to an appropriate food results in the generation of allergen-specific ige that occupies high affinity receptors for ige on the surface of mast cells and basophils resulting in allergic sensitization.55 re-exposure of the individual to this food results in binding of adjacent cell surface allergen-specific ige molecules, bridging of their high-affinity receptors, the explosive release of histamine, and the generation of newly formed mediators, some of which are chemo-tactic for eosinophils.55 an important translational study demonstrated that eoe represents a tH2-type allergic response. in this report, the investigators demonstrated the presence of ige-bearing mast cells within the epi-thelial cell layer of patients with eoe and identified potential allergens inducing the inflammatory response.56 an ige-mediated allergic reaction occurs within minutes to hours of allergen exposure.55 By contrast, non-ige-mediated allergic reactions typically orchestrated by tH2 lymphocytes are slower in onset, evolving over hours and days after food allergen exposure, resulting in eosinophil accumulation and symptoms localized to the gastrointestinal tract. this delay in symptom onset following food allergen exposure complicates accurate identification of offending foods in non-ige mediated food allergy. eoe symptoms are often consistent with those seen in non-ige mediated allergic reactions in that they are localized to the gastrointestinal tract and often delayed rather than immediate in onset.
eoe is considered to be a combined disorder in which both ige-mediated and non-ige-mediated immune mechanisms are involved. as a result, methods used to diagnose ige-mediated food allergy, such as skin-prick testing and the measurement of serum food allergen-specific ige levels are useful in identifying potential culprit foods, but will not detect those causing symptoms through a non-ige mediated mechanism. atopy patch testing (aPt), where food allergen extracts are placed in constant contact with the skin under 12 mm aluminum chambers for 48 h then removed and the sites of exposure examined for a reaction at 72 h, has been proposed as a method for potentially identifying foods causing symp-toms of eoe through a non-ige mediated mechanism. spergel and colleagues have reported substantial success as evidenced by biopsy-documented improvement in patients placed on elimination diets on the basis of information obtained through a combina tion of allergy skin-prick testing and aPt.48,57 the most common foods identified through patch testing by spergel et al. in their cohort were milk, wheat, corn, beef, egg, potato, chicken, soy, barley, oat and rice. 58 in this cohort the combined negative predictive value of allergy skin-prick testing and aPt for milk was considered unacceptably low, leading the authors to recom mend consideration of milk elimina tion even when testing to milk was nega-tive.58 Despite the promising findings reported by spergel and colleagues, some features have hindered wider use
of these tests, including a lack of standardization of the procedure, and the time and expertise required to accurately perform such tests.59
improvement of eoe following the use of food elimina tion diets emphasizes the significant causal role that food allergy has in most patients. symptom resolution and normalization of esophageal biopsies has been achieved in more than 95% of children with eoe on elemental diets.51 Difficulty in maintaining compliance to an elemental diet in adult patients, and the effect of such a diet on quality of life owing to the poor palatability and expense of these formulas has fos-tered the exploration of alternative dietary approaches. elimination of the six foods most commonly involved in eoe (dairy products, egg, wheat, soy, peanuts, fish/shellfish) without the performance of allergy testing led to disease remission in approximately 74% of patients.60 Food elimination diets based on the combined results of allergy skin-prick testing and aPt are known to be effective for inducing remission in the majority of patients with eoe.48,57,58 the marked improvement in symptoms noted upon removal of culprit foods from the diet underscores the effect that food-allergen exposure has in eoe.
a thorough history and assessment of allergic diseases is a vital part of the evaluation of a patient with suspected eoe because of the increased frequency of comorbid allergic disease, and the fact that allergens probably have a role in pathogenesis of this disease. Consultation with an allergist is indicated to aid in identifying, character-izing and treating comorbid allergic disease, in addition to identifying those allergens that are potential contribu-tors to esophageal inflammation.53 the allergist should aid in the development and monitoring of response to food elimination diets, as well as participating in the patient’s long-term management.
Clinical presentation significant variation exists in the clinical presentation of children and adults with eoe. whether this varia-tion is due to differences in the ability of these groups to enunciate discomfort or represents different disease stages is not yet certain. regardless of age, if a patient develops GerD-like symptoms and is not responding to treatment, whether that be pharmacological or surgi-cal, strong consideration should be given to a diagnosis of eoe.1,61
Children Children with eoe present with a broad range of non-specific symptoms that affect the upper gastrointestinal tract and respiratory tree.62–68 in the largest pediatric study to date of 381 children, liacouras et al. reported that the most common symptoms of eoe were divided into GerD-like symptoms and dysphagia. GerD-like symptoms predominated in this study (312 children) and included vomiting, regurgitation, abdominal pain, heartburn and water brash.51 of the remaining 69 children with
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dysphagia, 24 had radiological evidence of esophageal narrowing, but only one had an endoscopic stricture that required dilatation. these observations support the theory that symptoms related to eoe represent two differ ent disease phenotypes.
some patients with eoe experience acute symp-toms due to intermittent esophageal spasm, probably related to smooth-muscle contraction.69 nurko and col-leagues reported that of eight children with eoe and radio logical evidence of schatzki ring, none showed evidence of esophageal narrowing at the time of endo-scopy.70 measures of esophageal contraction recorded by 24 h motility monitoring were reported to be dis-ordered in 13 children with eoe compared with chil-dren with GerD and healthy controls.71 By contrast, chronic symptoms of dysphagia might reflect long-standing esophageal remodeling that occurs secondary to chronic eosinophilic inflammation. this tenet is sup-ported by the findings of isolated proximal and distal esophageal strictures, esopha geal rings, long-segment narrowing of the esophagus, and esophageal fibrosis in patients with eoe.72–92
an important subgroup of children with eoe have feeding difficulties that include refusal to eat, chewing problems, choking on solids or liquids, or an in ability to tolerate diet beyond certain textures or tastes.93
Frequently these symptoms are overlooked in the context of a busy practice but they may represent one of the first clues to the diagnosis of eoe. Feeding difficulties may represent acute esophageal dysfunction with pain, or chronic learned behavior from longstanding disease. a family history of eoe, dysphagia or food impaction may be present in children with the disease; it is not unusual for new diagnoses within a family to be uncovered during the evaluation of a child.94–98
Adults in contrast to children, most adults with eoe present in a stereotypical fashion with either food impaction or dysphagia.1,27,99 Food impaction at initial presentation, and especially at recurrent presentations, should alert the clinician to a possible diagnosis of eoe.27,80,83,84,100–104 Desai et al. found that eoe was the primary cause of food impaction in patients in a suburban private prac-tice setting.27 of 31 adults presenting with acute food impaction, 17 showed clinicopathological features of eoe. in addition, a study from the swiss esophageal esophagitis Databank reported that 35% of 251 adults with eoe presented with food impaction.27,84,85,102–107 of these patients, transmural perforation occurred in two patients who underwent rigid endoscopy and one patient experienced an esophageal rupture. in eoe, dys-phagia can be longstanding, dating back to childhood, or acute in onset. in a study of 30 patients with eoe who were followed up for over 11 years, dysphagia was the predominant complaint and persisted and posed major problems in the patients’ lifestyles.83 as eoe has been increasingly recognized by clinicians, reports of
acute and severe chest pain probably related to esopha-geal spasm have become associated with the disease (G. t. Furuta, personal communication).
Diagnosis Physical examination Physical examinations are important to rule out other causes for esophageal eosinophilia, such as iBD, and to identify co-morbid allergic diseases.108 no patho-gnomonic findings on physical examination have been reported in eoe. white plaques commonly observed in the esophageal mucosa of patients with eoe have not been observed in the oropharynx.109 evidence of mucosal disruption is rarely observed.110
identification of signs of allergic diseases, including allergic rhinitis, asthma and eczema, may be present and prompt further evaluation and treatment.
Laboratory analysis no single biomarker of eosinophilic inflammation pro-vides support for or against the diagnosis of eoe.111 if anemia, elevated erythrocyte sedimentation rate or serum levels of C-reactive protein, or markers of other systemic illness are identified, a search for an alternative diagnosis other than eoe should ensue. Peripheral eosinophilia is not a reliable sign for eoe as it is not always present.1,112 when identified, it is difficult to differentiate whether peripheral eosinophilia occurs as a marker for eoe or other comorbid diseases.
Konnikoff et al. reported that the combination of peripheral eosinophilia with elevated serum levels of eotaxin-3 (CCl26) and eosinophil-derived neurotoxin correlated with increased esophageal eosinophil density and thus may provide a biomarker panel for monitor-ing eoe.113 in their study of 47 children, these three bio-markers correlated with esophageal eosinophil density. Further validation of these studies will be important, because such markers could potentially eliminate the necessity of performing repeated endoscopies and biopsies in patients with suspected eoe.
Radiological assessment the use of contrast radiography serves two purposes in the evaluation of a patient with suspected eoe. upper gastrointestinal radiography is useful to eliminate other causes of vomiting, such as anatomical malformations. in addition, barium studies can provide important informa tion regarding the presence of esophageal stric-ture or long-segment narrowing.79,80,114 some of the first reports of eoe arose from the radiological litera ture that described single and multiple esophageal rings.73,74,115 Communication between the gastro enterologist and the radiologist is important as esophageal strictures may be proximal and long- segment narrowing can be missed on radiography, as it can encompass much of the length of the esophagus. schatzki rings are also occasionally visualized on radio graphy but may be absent at endo-scopy showing that this finding represents a transient
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esophageal contraction.71 another study found schatzki rings not to be associated with eoe.116
Endoscopic features a number of endoscopic features associated with eoe have been reported.69,110 loss of vascular pattern and longitudinal furrowing of the esophagus (Figure 1) probably represent epithelial edema.117 white exudates (Figure 2) are the gross manifestation of eosinophilic pus and correlate with the histological finding of eosino-philic abscesses.110,118–120 Concentric rings (Figure 3) may be transient, indicating esophageal contraction, or fixed, indicating tissue remodeling with stricture forma-tion.75,82,87,90,121–125 when esophageal pinch biopsies are obtained, the mucosa may feel rubbery at inflamed sites owing to fibrosis, thus making tissue samples more diffi-cult to obtain compared with noninflamed sites.110 long-caliber esophageal narrowing or small-caliber esophagus is observed infrequently in eoe and may only be recog-nized after removal of the endoscope when longi tudinal shearing and/or splitting of the mucosa or crepe paper esophagus is evident (Figure 4).77,80,114 Perforation is unusual but has been reported.88,91,126–129 esophageal erosions and friability are rarely seen.83
Histological features eoe is characterized histologically by dense epithelial eosinophilia (Figures 5 and 6).130 the limited size of endoscopic mucosal biopsies (3 mm in diameter or less) prevent characterization as to the depth of this inflamma-tion, but ultrasonographic and limited surgical reports suggest deep involvement.131–133 one study demonstrates the importance of obtaining multiple biopsies (five) to ensure accurate diagnosis.134
Diagnosis of eosinophilia is focused primarily on the peak number of eosinophils per high-power field (HPF) present in the epithelial surface; the most sensitive and specific threshold number of eosinophils (peak or mean) in the mucosal biopsy that correctly identifies patients with eoe continues to be a matter of discussion.1,130 this issue is complicated by many factors, including variable size of individual HPFs examined, differences in the definition of the cellular morphology that constitutes an intact eosinophil, and the number of HPFs that should be assessed.135 to address this issue, the north american society of Pediatric Gastroenterology and nutrition initiated the development of consensus recommenda-tions to identify a diagnostic algorithm for eoe. Clinical expertise and data from the literature were reviewed at the First international Gastrointestinal eosinophil research symposium (FiGers) and the results of this symposium and review were recently published.1,136 as a part of this process, ≥15 eosinophils per single HPF was chosen as the threshold number for the diagnosis of eoe with one important caveat: as discussed earlier, alternative etiologies, in particular GerD, must be ruled out as a cause for this inflammation.11,137 in the future, additional pathological criteria and techniques
will be identified to increase the specificity and sensi-tivity of diagnosis of eoe, and will prompt revisions to these recommendations.138
epithelial surfaces affected by eoe may also demon-strate features such as superficial layering of eosinophils and microabscesses on the superficial layer (Figure 5);139
these findings are the histological representations of the endoscopic feature termed white exudates or eosinophilic pus (Figure 2).109,118
eosinophil degranulation occurs significantly more often in adult patients with eoe than in those with GerD.27,140–142 Degranulation can be extensive and may represent the only identifiable footprint or ghost of eosinophils that resided in a microscopic field. in this regard, eosinophilic inflammation and degranulation are often patchy in eoe and offer new opportunities to add to the diagnostic algorithm. For example, Prothroe et al. reported the use of a novel eosinophil peroxidase anti-body scoring system that used patterns of degranulation and eosinophil number as rubrics for analysis of mucosal
Figure 1 | Longitudinal furrowing or ridging, loss of vascular pattern with a scant amount of white papular exudates in the midesophagus of a patient with eosinophilic esophagitis.
Figure 2 | extensive, confluent patches of white exudate in the distal esophagus of a patient with eosinophilic esophagitis. This finding was associated with severe eosinophilic infiltration on subsequent biopsy.
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biopsies from adults with eoe.143 in this retrospective study, they were able to reliably discern eoe from GerD based solely on these histological features.
other commonly identified histological features observed in children and adults with eoe include basal zone hyperplasia, rete peg elongation, intracellular edema, and dilated intercellular spaces (Figure 6).130 in combination with other features of inflammation, these findings may also help to segregate eoe from other sources of esophageal inflammation. Finally, evidence shows that lamina propria fibrosis is present in mucosal biopsies obtained from children with eoe. studies in this regard are limited by the fact that endoscopi-cally obtained biopsies rarely contain enough lamina propria for examination and a validated esophageal fibrosis scoring system is lacking. aceves et al. reported increased fibrosis in trichrome-stained samples from
seven children with eoe compared with samples from children who had GerD.144 with regard to the logical pathology and physiology of this process, the investi-gators identified increased expression of transforming growth factor β and increased evidence of its cognate signaling molecule phospho-smaD in patients with fibrosis. Chehade et al. revealed similar findings upon comparing 21 children with eoe with six with GerD, and 17 healthy controls.29 interestingly, in both of these studies, some healthy controls showed evidence of fibrosis.
treatment Clinicians use two very different end points for the treat-ment of eoe: symptom relief only (clinical remission) or symptomatic relief and histological remission (clinical and pathological remission).145 the latter approach is complicated by the fact that the definition of histological remission varies between clinicians. while the esophagus typically does not contain resident eosinophils, no studies have determined a threshold number of eosinophils that may be tolerated, if any, in the esophageal epithelium of an eoe patient following treatment.
the rationale for seeking only clinical remission is that as limited data are available regarding the natural history of the disease,146 the cost and morbidity associ-ated with post-treatment endoscopy and the overall psycho logical effect of treatments, it is difficult to justify chronic treatment and repeated endoscopies.145 However, many physicians seek to achieve clinical and pathological remission. a growing body of clinical experi ence has shown that patients may still have signifi-cant esophageal inflamma tion despite experi encing few or no symptoms.147 in these circumstances, it is impos-sible to predict which patients will develop complica-tions, such as esophageal remodeling with isolated or long-segment narrowing, and when they will develop complications. thus, many clinicians feel that the threat of ongoing inflammation and subsequent esophageal remodeling consequences outweigh the risks of repeat endoscopic evaluation.145
as the exact incidence and breadth of esophageal complications in patients with eoe have not been deter-mined, and the effects of chronic treatments and endo-scopy have not yet been measured, each clinician will need to make a decision as to the approach or combina-tion of approaches that should be used for the treatment of eoe.148 Future studies will provide more guidance in this area of controversy.
although the end point of treatment is a matter of debate, at least two safe and effective treatments have been identified (Box 2). the reader is referred to a number of reviews on this topic for further details regard-ing the specifics of each treatment.149–151 regardless, evi-dence suggests that eoe is a chronic disease and without ongoing treatment, symptoms and inflammation will return or persist. no pharmacological maintenance treatment has yet been identified.1
Figure 3 | Concentric rings with a white papular exudate in the proximal esophagus of a patients with eosinophilic esophagitis.
Figure 4 | Longitudinal shearing and/or splitting, termed crepe-paper esophagus in an adolescent patient with eosinophilic esophagitis.
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Pharmacological therapy two lines of evidence support the use of systemic and topical steroids for the treatment of children and adults with eoe. First, corticosteroids significantly reduce syn-thesis of eosinophil growth factors (il-5, granulocyte macrophage colony-stimulating factor) and chemo-attractants (eotaxin-3 [CCl26]) and induce eosinophil apoptosis.152 second, longstanding clinical experience has shown that eosinophilic inflammation in allergic and inflammatory responses is responsive to treatment with steroids.153,154
in this regard, liacouras et al. reported the first successful use of corticosteroids (1–2 mg/kg daily for 2–4 weeks) in achieving clinical and pathological remis-sion in 21 children with eoe.153 when treatment was completed and steroids withdrawn, disease returned. Faubion et al. first reported on the use of topical cortico steroids for eoe in 1998.155 in an effort to reduce children’s systemic steroid exposure, this group used a metered dose inhaler to administer a topical prepara-tion of budesonide or fluticasone to children with eoe. Four children received sprays of the metered dose inhaler in the mouth (without inhaling and without a spacer) 2–4 times daily for 4–8 weeks, and experienced remission of symptoms. teitelbaum et al. demonstrated clinical and pathological success as well as a reduction of CD8+ lymphocytes in 11 children with eoe after 8 weeks of fluticasone treatment.31 Konnikoff et al. performed the only double blind, placebo-controlled trial of treatment for eoe, in which 36 children were randomly allocated to receive fluticasone or placebo over a 3-month period.156 remission was achieved in 55% of fluticasone-treated children and 9% of placebo-treated children; the greatest effect of this treatment was shown in the proximal esophagus. other studies have shown a similar response in adult patients with eoe treated with steroids, and that topical steroids can downregulate cytokines implicated in the pathogenesis of eoe, including eotaxin-3 (CCl26) and il-5.157–159 a 2007 study revealed the beneficial effect of this steroid treatment on the specific eoe inflammatory trans-criptome.160 in an effort to improve the delivery of ste-roids, aceves et al. mixed budesonide with sucralose to make a viscous slurry.161,162 ingestion of this product led to clinical and pathological remission in 16 of the 20 children who were studied.
side effects of steroid treatment include well-known complications, such as bone demineralization, cata-racts, growth inhibition, diabetes, acne, and mood dis-turbances.1,163 oral and esophageal candida and herpes infections have been reported with the use of topical steroids in a limited number of patients with eoe.31,164
therapeutic agents that are currently being investi-gated include anti-il-5 monoclonal antibody.165 as il-5 is critical to the growth and development of eosinophils, il-5 is increased in the esophageal mucosa of patients with eoe, and murine studies show the il-5 dependency of eoe, anti-il-5 therapy may benefit patients. one
study has shown anti-tumor necrosis factor therapy to be ineffec tive for the treatment of eoe.1,166
Dietary therapy at least three lines of evidence support a role for nutritional treatment in eoe. First, animal models have demon strated that eosinophilic gastrointestinal inflamma tion can be induced by food sensitization.167
Figure 5 | esophageal mucosa of a patient with eosinophilic esophagitis showing large numbers of eosinophils scattered throughout the epithelium in a diffuse pattern with microabscess formation on the superficial layer, and evidence of degranulation throughout (×40 magnification).
Figure 6 | esophageal mucosa of a patient with eosinophilic esophagitis showing large numbers of eosinophils with evidence of superficial layering, basal zone hyperplasia and rete peg elongation (×40 magnification).
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second, a number of studies and clinical experiences link food allergies with allergic diseases, such as eczema, and eosinophilic gastrointestinal diseases, such as eoe.168 Finally, use of an amino-acid-based diet formula and in some cases, dietary exclusions, leads to clinical and pathological remission of eoe.51,65,169
in 1995, Kelly et al. published the first study demon-strating the successful use of an elemental dietary formula for the treatment of eoe in children.64 after receiving at least 8 weeks of an amino-acid-based dietary formula, 10 children achieved clinicopathological remission, and experienced a recurrence of symptoms upon the reintro-duction of foods. since then, other studies and clinical experience have shown similar results with the use of elemental dietary formulas. in an effort to provide a tar-geted approach to dietary therapy and to liberalize the diet of affected patients, removal of single or multiple foods has been attempted. spergel et al. used skin-prick and skin-patch allergy testing to identify allergenic foods in 26 children with eoe.48 in this study, 18 children had symptom resolution after food removal. Finally, to elimi-nate allergy testing all together, Kagalwalla et al. removed the six most common food allergens from the diets of 35 children with eoe and demonstrated that after 6 weeks of this diet, over 75% achieved clinical and pathological remission.60 similar results were reported by Gonsalves et al. in 2007.170
Dietary management can influence patients’ lives in a number of ways. when eliminating any food product from the diet of any patient, especially that of a child, a dietician must be involved to insure that a properly balanced nutritional plan is provided.171,172 the cost of special diets, especially those composed of elemental formulas, can be significant and reimbursements are often not provided. Diets can also affect psychosocial aspects (dating, birthday parties, school and profes-sional activities) of patients’ lives. these factors all need to be considered and discussed with families before dietary therapy is initiated to maintain a balance between
sometimes difficult treatment plans and long-term treatment outcomes.173
Esophageal narrowing an unknown proportion of children and adults with eoe develop esophageal strictures or small-caliber esopha-gus.174 it is important to remember, as mentioned earlier, that the radiographic appearance of a schatzki ring or the endoscopic view of concentric esophageal narrowings may actually represent a transient esophageal contrac tion.71 these findings may not require mechanical dilatation, but rather pharmacological or nutritional management.
if an esophageal stricture or long-segment narrowing of the esophagus is identified, two approaches, mech-anical dilatation or pharmacological treatment with corticosteroids, have been used.127,175–177 when strictures are untreatable with pharmacological therapy, dilatation with a bougienage may be necessary. it is not uncommon for the endoscope itself to accomplish dilatation merely with its initial passage. the advantages of a mechanical approach are immediate relief of the partial obstruction. in contrast to dilatation of a peptic stricture, esophageal dilatation should be performed gently and may require multiple sessions to achieve satisfactory results. the disadvantage of this therapy is the potential for esopha-geal perforation and pain severe enough to, in some cases, require hospitalization. systemic steroids may be administered as first-line therapy in some patients with strictures, and mechanical dilatation performed subsequently if no response is observed. the advan-tage of this approach is that the steroid may reduce the acute inflamma tory response. the efficacy of inject-ing esophageal strictures with corticosteroids has not been reported.
Conclusions eoe is a chronic esophageal inflammatory disease of undetermined pathology and physiology. in childhood, vague symptoms associated with GerD and feeding difficulties are the first manifestations. adults typically present with dysphagia and food impaction. no patho-gnomonic features of eoe have been identified and, therefore, its diagnosis must be made on both clinical and histological grounds. effective treatments rely on ster oids and dietary exclusions. treatments under investi-gation include anti-il-5 therapy. Future studies that focus on the natural history of the disease, the quality of life of patients with the disease, molecular pathogenesis and novel treatments will improve care for children and adults with eoe.
Review criteria
references for this review were identified by searches of PubMed for articles published between 1960 and 2008 with the terms “eosinophilic esophagitis”, “eosinophilic esophagitis”, and “esophageal eosinophilia”. Only papers published in english were reviewed. The reference list was updated in February 2009.
Box 2 | Treatments for eosinophilic esophagitis
Dietary
single or multiple food exclusions
elemental diet formula
pharmacological
systemic corticosteroids
Prednisone 1 mg/kg once daily ■
Topical steroids ■
Fluticasone 220 mg, 2 oral puffs orally twice daily ■(adults)
No use of spacer, no rinsing of mouth, no eating or drinking for 30 min after administration
Novel biological agents
Anti-interleukin 5 ■
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acknowledgmentsThis work was supported by the Campaign for Urgent research on eosinophilic Diseases (CUreD) and the Pappas Foundation.
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