www.elsevier.com/locate/jpedsurg

Journal of Pediatric Surgery (2008) 43, 810–814

Eosinophilic esophagitis and intermediate esophagitis aftertracheoesophageal fistula repair: a case seriesCarol Oliveiraa, Mohammed Zamakhsharya,b, Peggy Marconc, Peter C.W. Kima,⁎

aDivision of General Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8bDivision of Paediatric Surgery, King Abdulaziz Medical City-Riyadh, Saudi ArabiacDivision of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

Received 16 November 2007; accepted 3 December 2007

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Key words:Eosinophilic esophagitis;Intermediate esophagitis;Eosinophilia;Tracheoesophageal fistula;Esophageal atresia;Food allergies;Atopy;Gastroesophageal reflux

AbstractBackground: Eosinophilic esophagitis (EE) is often missed or underdiagnosed in children, particularlyin the setting of reflux disease associated with tracheoesophageal fistula (TEF). Intermediate esophagitis(IE) is a recently described condition, which includes characteristics of gastroesophageal reflux diseaseand EE but does not present with enough eosinophils on biopsy to diagnose EE. Here we present a caseseries of EE and IE associated with TEF, and their clinical manifestations.Methods: A retrospective analysis including clinical presentation, endoscopic and pathologic findings,and treatment of 4 patients with EE and 4 patients with IE who presented between 2003 and 2007 wasperformed.Results: Male dominance was found equally in both groups (75%), and most patients had a personalhistory of atopy (87.5%). Food allergies were seen mainly in the EE group (75%). The most frequentprimary symptoms in both groups were dysphagia for solids (75%) and for liquids (25%). The median ageat diagnosis was 9.8 vs 11.2 years in the EE and IE groups, respectively. On endoscopy, both groups hadsimilar findings including furrows (EE, 75%; IE, 66.6%) and white plaques (EE, 50%; IE, 33.3%). In bothgroups, almost all patients had basal cell hyperplasia on biopsy (EE, 100%; IE, 75%). Degranulatedsurface eosinophils (50%) and eosinophilic abscess (25%)were found in the EE group only. Elongated retepapillae were more often seen in EE biopsies (50%) compared with IE biopsies (25%). Peripheral serumeosinophilia was seen in all EE patients and in 33% of the IE patients. The only effective treatment withcomplete resolution of the symptoms was the topical or systemic application of steroids.Conclusions: The diagnosis of EE and IE is frequently missed or delayed. Eosinophilic esophagitisshould be suspected in reflux disease refractory to conventional treatment, particularly in the settingof TEF. Intermediate esophagitis represents an entity that includes findings of gastroesophageal refluxdisease and EE. Endoscopic biopsies are diagnostic for both conditions and allow institution ofspecific medical treatment.© 2008 Published by Elsevier Inc.

Presented at the 39th Annual Meeting of the Canadian Association ofediatric Surgeons, August 23-26, 2007, St John's Newfoundland, Canada.⁎ Corresponding author. Tel.: +1 416 813 6357; fax: +1 416 813 7477.E-mail address: peter.kim@sickkids.ca (P.C.W. Kim).

022-3468/$ – see front matter © 2008 Published by Elsevier Inc.oi:10.1016/j.jpedsurg.2007.12.018

With improved and expectant survival after the surgicalrepair of tracheoesophageal fistula (TEF), the long-termfollow-up and management of morbidity are increasinglybecoming clinically relevant in the post-TEF repair period

Table 1 Differences between EE and IE

EE IE

Median age at diagnosis ofEE/IE (range)

9 y 8 mo(4 y-13 y 4 mo)

11 y 2 mo(8 y 7 mo-15 y10 mo)

History: Environmental/seasonalallergies

75% 25%

Food allergies 75% 0%Familyhistory:

Food allergies 0% 50%

Endoscopy: Difficultypassingendoscope

50% 0%

Bloodwork:

Eosinophilia 100% 33%Eosinophiliccount 0.5-1/N1

75%/25% 0%/100%

Table represents a selection of the most significant results.

811EE and IE after tracheoesophageal fistula repair

[1]. Presenting symptoms of some of these gastrointestinalmorbidities include dysphagia (50%), respiratory tractinfections (29%), and gastroesophageal reflux disease(GERD) (25%-75%) [1]. Eosinophilic esophagitis (EE) hasbeen recently described in the literature as a separate entityfrom GERD and intermediate esophagitis (IE) [2,3]. Becausepresenting symptoms are similar to those of GERD,misdiagnosis or delayed diagnosis often occurs. Therefore,in children with persistent therapy-refractory GERD, parti-cularly in the setting of TEF and/or atopic conditions, EErepresents an important differential diagnosis from GERDrequiring pathologic differentiation based on infiltratingeosinophil counts: EE (N20 eosinophils per high-power field[HPF]), IE (5-19 eosinophils per HPF) and GERD (b3eosinophils per HPF).

The association of TEF to EE has been underreported [4].Here we report the results of our long-term follow-up ofpatients with EE and IE in TEF population.

1. Methods

With a Research Ethics Board approval, a retrospectiveanalysis of all TEF cases between May 2003 and January2007 was performed. Eight patients were identified afterupper endoscopy with biopsy. The indication for endoscopywas nonresponse to medical treatment of GERD. Patientswere diagnosed and assigned to either the EE or IE groupbased on the pathologic findings. The clinical presentation,endoscopic and histologic findings, and treatment of the 4patients of each group were evaluated. Primary symptomsnecessitating the initial referral were recorded.

Patients with more than 20 eosinophils per HPF werediagnosed with EE. Eosinophilic count between 5 and 19eosinophils per HPF was considered IE. Secondary histolo-gic findings like basal cell hyperplasia or elongation of retipapillae were not crucial for diagnosis. Other diagnostic testssuch as blood work and 24-hour pH probes were performeduniformly on all patients in our series.

2. Results

2.1. Demographic data

Eight patients with TEF repair as neonates were included.Four had EE and 4 had IE based on the aforementionedclassification. Male dominance was seen in both groups(75%). The ethnic background was predominantly Caucasianin both groups. The median age at diagnosis was 9.7 years(range, 4-13.4 years) vs 11.3 years (range, 8.6-15.9 years) forthe EE and IE groups, respectively (Table 1). Interestingly,1 in 4 patients had pure esophageal atresia (TEF anomalytype 1) in both groups. Fifty percent of EE patients had a

history of prematurity compared with only 1 patient in the IEgroup. Associated anomalies included the full spectrum ofthe VACTERL syndrome. The IE group had more associatedmalformations than the EE group.

2.2. Presenting symptoms

Dysphagia was universal in both groups. Dysphagia tosolids was seen in 75% of cases. Vomiting was a predominantsymptom in 50% of the patients in the EE group, whereasonly 1 patient in the IE group had significant vomiting. Inboth groups, failure to thrive was present in 25% of thepatients. Chest pain was more often found in the IE group(EE, 25%; IE, 50%). Constipation and epigastric pain wereonly present in the IE group (50% and 25%, respectively).

Virtually all patients of either group had an atopiccondition. Asthma was found in 75% of the patients of bothgroups, whereas environmental and seasonal allergies werepredominant in the EE group (75% and 25%). One patient inthe EE group had eczema. Interestingly, food allergies wereexclusively seen in the EE group (75%). Furthermore, allpatients had GERD as an infant or later. Stricturesnecessitating dilation were present in 50% of the EE patientsvs 25% of the IE patients. A family history of atopy waspresent universally. Family history of food allergies was notdemonstrated in any of the patients in the EE group, whereassuch a history was present in 50% of the IE group (Table 1).

2.3. Diagnostic considerations

Anemia was observed in 50% of the EE group comparedwith 25% of the IE group. Interestingly, a peripheraleosinophilia was found in all patients of the EE group,with an eosinophilic count of 0.5 to 1 in 3 patients and N1 in1 patient. One patient of the IE group had a peripheraleosinophilia with a total eosinophilic count of N1.

Table 2 Findings on endoscopy and biopsy

EE IE

Endoscopy: Difficulty passing endoscope 50% 0%Normal esophageal mucosa 0% 25%Esophageal furrows 75% 66%White plaques in the esophagus 50% 33%Pale appearance of the esophagus 25% 0%Hiatus hernia 0% 25%Gastritis 25% 25%Duodenitis 25% 0%

Biopsy: Eeosinophilic abscess 25% 0%Degranulated surface eosinophils 50% 0%Elongated reti papillae 50% 25%Gastritis 50% 75%Duodenitis 25% 0%H pylori 0% 0%GERD findings 75% 75%

812 C. Oliveira et al.

Barium swallows were abnormal in all subjects. Seventy-five percent of EE patients and 50% of the IE patients haddysmotility, and only 1 EE patient had a mild stricture. The24-hour pH probe was abnormal in all IE patients and in 75%of EE patients, with an accentuation of the pathologicfindings in the IE group.

All patients in our series underwent a diagnosticendoscopy. Fifty percent of EE patients needed a smallerendoscope than what would be normally expected. This wasnot the case in the IE group. Only 1 patient had a normalmucosa of the esophagus on endoscopy (IE patient). Theendoscopic findings of our patients are consistent with thosedescribed in literature, which are strictures, mucosal rings,furrowing, corrugation, ulceration, and white plaques [5-7].The most common findings were furrows (EE, 75%; IE,66.6%), white plaques (EE, 50%; IE, 33.3%), and a paleappearance (EE, 25%). One patient had a hiatal hernia (IEpatient). Nonspecific mucosal changes of the stomach werefound in 25% of both groups. The duodenum was abnormalon endoscopy in 1 patient of the EE group (Table 2).

On biopsy, more than 20 eosinophils were seen in thelower and middle esophagus in EE patients. One EE patienthad less than 5 eosinophils in the upper esophagus. Incontrast, IE patients had less eosinophils all over theesophagus. Almost all patients had basal cell hyperplasia,and no patients had ruptured eosinophils. Degranulatedsurface eosinophils (50%) and eosinophilic abscess (25%)were only found in the EE group. Elongated reti papillaewere more often present in EE biopsies (50%) than in IEbiopsies (25%). Remarkably, none of the 8 patients waspositive for Helicobacter pylori. Eosinophils were found in 1duodenal biopsy of an EE patient.

2.4. Treatment

Proton pump inhibitors were effective in 2 of 3 EEpatients and in 75% of IE patients. H2 blockers reduced

symptoms in 1 of 2 EE patients. Prokinetic agents had noeffect on the symptoms of our patients. Steroids were theonly effective treatment modality.

The local (swallowed inhalation steroids) or systemicapplication of steroids led to complete resolution ofsymptoms in all patients. A reduction of symptoms wasachieved with montelukast (EE, 4/4; IE, 1/1). However, mostof the patients needed steroids over the course of their illness(EE, 3 of the 4 patients who had montelukast; IE, 1 of 1).None of our patients had dietary modifications as part of theirtreatment.

3. Discussion

To the best of our knowledge, there have been no otherreports of EE in the setting of TEF in the surgical literature.The TEF patients as a group have a high incidence ofassociated GERD, which causes significant long-termmorbidity [1]. In a significant minority of the patients,GERD-like symptoms fail to subside despite maximaltherapy. One consideration in TEF patients with refractoryGERD should be eosinophilic disease. In this study, wecompared patients with EE with those with IE, both of whichare relatively new diagnostic disease entities. The initialpresentation, workup, and endoscopic and histologic find-ings were also compared.

The chronic inflammation caused by GERD is usuallyrestricted to the mucosa of the esophagus, whereasinflammation caused by EE affects all 3 layers [3]. Therefore,a higher rate of stricture formation and dysmotility in EEwould be expected compared with GERD. Symptoms ofGERD, such as heartburn, chest and epigastric pain, andwater brash, were of secondary importance in making thediagnosis of EE, but prevalent in the IE group. This mayreflect the less important role of GERD in EE compared withIE. However, an incomplete resolution and persistence ofsymptoms despite medical and surgical antireflux therapyshould raise a suspicion for EE [7]. The incidence of EE inchildren with GERD refractory to antireflux treatment hasbeen described as 8% to 10% [3].

The previously documented high incidence of atopy in EEpatients was in keeping with our findings. Asthmarepresented the most common atopic condition (75%).Interestingly, food allergies were only found in the EEgroup, which may imply a stronger impact of food allergieson the pathogenesis of EE compared with IE. All of ourpatients had a history of GERD, but it remains unclearwhether GERD is crucial for the pathogenesis of EE or not.Family history of EE patients is usually positive for atopicdiseases as well as for esophageal strictures and EE itself[5,8]. In our series, family history included atopic diseases(EE, 2 patients; IE, 3 patients); but none of our patients had afamily history of strictures or EE. Although the pathogenesisof EE is not fully understood, there is good evidence to

813EE and IE after tracheoesophageal fistula repair

support a theory implicating IgE-mediated and T-cell–drivenallergic reactions against food and seasonal allergens beingcrucial for the development of EE [9-11]. Food allergies inparticular are thought to induce and exacerbate EE[2,6,7,9,12]. Milk, egg, wheat, and soy are the most commonallergens related to EE [13-15]. Because the origin of EE isthought to be—at least in part—of atopic nature, skin pricktest and atopic patch test are sometimes of diagnostic value[7,14]. However, the predictive value of both tests showsgreat variability [7,9,13,14]. The difference in prevalence ofperipheral eosinophilia of both groups (EE, 100% vs IE,25%) supports the theory of IE being a less distinctive formof EE.

It is important to note that biopsy is crucial for thediagnosis of EE and IE [3,5,9,14]. Furthermore, it is crucialfor a proper diagnosis of EE to take biopsies fromwidespread locations because EE is described as a patchydisease process [8]. The most important criterion is thepresence of eosinophils, which are normally absent in theesophagus [5,7,14]. Twenty or more eosinophils per HPF inthe squamous mucosa indicate EE [5,6,13,14]. Anotherclassification accepts N15 eosinophils per HPF as beingconsistent with EE, 3 to 15 eosinophils with IE, and b3eosinophils with GERD [3].

Additional feature for the differentiation between EEand GERD is the extent of basal layer hyperplasia [13,16].No significant difference in the presence of basal layerhyperplasia was noted between the 2 groups in our series.Although EE is usually distributed equally throughout theesophagus, our EE patients showed an accentuation ofeosinophils to the lower and mid esophagus, which istypical of GERD [3,8]. Activated mucosal mast cells canbe found in addition to the eosinophils [2,11]. In our studypopulation, in addition to the number of eosinophils,discriminating histologic findings between the 2 groupswere degranulated surface eosinophils and eosinophilicabscess with predominance in the EE group. Helicobacterpylori, which is responsible for inducing gastritis andduodenitis, was not present in any of the biopsyspecimens. Nevertheless, nonspecific gastritis was presentin some patients. A correlation between EE and eosino-philic gastritis/duodenitis has been described before [10].Further biopsies need to be done to follow a possibleprogression of IE into EE and to define the natural historyof this new entity.

Treatment options for EE are elemental and eliminationdiets, and systemic or local steroids [5,6,14,17]. Agents suchas montelukast (leukotriene antagonist), cromolyn (mast cellstabilizer), and mepolizumab (anti–interleukin-5) may playan increasing role in the management of EE [3-6].Leukotriene, interleukin-5, and mast cells are crucial in theIgE-induced allergic reaction. Preventing their action is areasonable strategy of therapy for an allergic reaction in theesophagus. Aggressive antireflux treatment leads to animprovement of the symptoms in EE, but not to a reductionof the histologic findings [3]. Elemental diets are known to

resolve clinical as well as histologic findings in 95% of cases[14]. However, as would be expected, compliance is poorespecially in older children [14]. Alternatively, eliminationdiets with elimination of allergens confirmed by skin pricktest and atopic patch test can be applied and may resolvehistologic findings in up to 75% of cases [14]. Local steroidslead to resolution of the symptoms in 75% and to a remissionof histologic findings in 50% of cases [3,5,17]. Patients withstrong association to atopy are less responsive to topicalsteroids than others [7,17]. Generally, systemic steroidsresolve EE during the period of intake; but 35% relapse afterwithdrawal [5]. Our patients responded to steroids with areduction of symptoms, but further biopsies and follow-upneed to be done to describe the histologic effects and theoccurrence of relapses.

In conclusion, TEF patients have a high incidence ofGERD. Male patients of this group with persistent GERDrefractory to maximal medical and surgical therapy or withdysphagia should undergo a diagnostic endoscopy withbiopsies to exclude EE or IE. In particular, this is stronglyrecommended in patients with food or environmental/seasonal allergies or asthma. Data are needed to define thenatural history of IE in TEF patients.

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