Journal of Pediatric Surgery (2008) 43, 810–814
www.elsevier.com/locate/jpedsurg
Eosinophilic esophagitis and intermediate esophagitis after tracheoesophageal fistula repair: a case series Carol Oliveira a , Mohammed Zamakhshary a,b , Peggy Marcon c , Peter C.W. Kim a,⁎ a
Division of General Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 Division of Paediatric Surgery, King Abdulaziz Medical City-Riyadh, Saudi Arabia c Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 b
Received 16 November 2007; accepted 3 December 2007
Key words: Eosinophilic esophagitis; Intermediate esophagitis; Eosinophilia; Tracheoesophageal fistula; Esophageal atresia; Food allergies; Atopy; Gastroesophageal reflux
Abstract Background: Eosinophilic esophagitis (EE) is often missed or underdiagnosed in children, particularly in the setting of reflux disease associated with tracheoesophageal fistula (TEF). Intermediate esophagitis (IE) is a recently described condition, which includes characteristics of gastroesophageal reflux disease and EE but does not present with enough eosinophils on biopsy to diagnose EE. Here we present a case series 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 was performed. Results: Male dominance was found equally in both groups (75%), and most patients had a personal history of atopy (87.5%). Food allergies were seen mainly in the EE group (75%). The most frequent primary symptoms in both groups were dysphagia for solids (75%) and for liquids (25%). The median age at diagnosis was 9.8 vs 11.2 years in the EE and IE groups, respectively. On endoscopy, both groups had similar findings including furrows (EE, 75%; IE, 66.6%) and white plaques (EE, 50%; IE, 33.3%). In both groups, almost all patients had basal cell hyperplasia on biopsy (EE, 100%; IE, 75%). Degranulated surface eosinophils (50%) and eosinophilic abscess (25%) were found in the EE group only. Elongated rete papillae were more often seen in EE biopsies (50%) compared with IE biopsies (25%). Peripheral serum eosinophilia was seen in all EE patients and in 33% of the IE patients. The only effective treatment with complete 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 esophagitis should be suspected in reflux disease refractory to conventional treatment, particularly in the setting of TEF. Intermediate esophagitis represents an entity that includes findings of gastroesophageal reflux disease and EE. Endoscopic biopsies are diagnostic for both conditions and allow institution of specific medical treatment. © 2008 Published by Elsevier Inc.
Presented at the 39th Annual Meeting of the Canadian Association of Pediatric 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:
[email protected] (P.C.W. Kim). 0022-3468/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.jpedsurg.2007.12.018
With improved and expectant survival after the surgical repair of tracheoesophageal fistula (TEF), the long-term follow-up and management of morbidity are increasingly becoming clinically relevant in the post-TEF repair period
EE and IE after tracheoesophageal fistula repair [1]. Presenting symptoms of some of these gastrointestinal morbidities include dysphagia (50%), respiratory tract infections (29%), and gastroesophageal reflux disease (GERD) (25%-75%) [1]. Eosinophilic esophagitis (EE) has been recently described in the literature as a separate entity from GERD and intermediate esophagitis (IE) [2,3]. Because presenting symptoms are similar to those of GERD, misdiagnosis or delayed diagnosis often occurs. Therefore, in children with persistent therapy-refractory GERD, particularly in the setting of TEF and/or atopic conditions, EE represents an important differential diagnosis from GERD requiring pathologic differentiation based on infiltrating eosinophil counts: EE (N20 eosinophils per high-power field [HPF]), IE (5-19 eosinophils per HPF) and GERD (b3 eosinophils per HPF). The association of TEF to EE has been underreported [4]. Here we report the results of our long-term follow-up of patients with EE and IE in TEF population.
1. Methods With a Research Ethics Board approval, a retrospective analysis of all TEF cases between May 2003 and January 2007 was performed. Eight patients were identified after upper endoscopy with biopsy. The indication for endoscopy was nonresponse to medical treatment of GERD. Patients were diagnosed and assigned to either the EE or IE group based on the pathologic findings. The clinical presentation, endoscopic and histologic findings, and treatment of the 4 patients of each group were evaluated. Primary symptoms necessitating the initial referral were recorded. Patients with more than 20 eosinophils per HPF were diagnosed with EE. Eosinophilic count between 5 and 19 eosinophils per HPF was considered IE. Secondary histologic findings like basal cell hyperplasia or elongation of reti papillae were not crucial for diagnosis. Other diagnostic tests such as blood work and 24-hour pH probes were performed uniformly 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 aforementioned classification. Male dominance was seen in both groups (75%). The ethnic background was predominantly Caucasian in 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) for the EE and IE groups, respectively (Table 1). Interestingly, 1 in 4 patients had pure esophageal atresia (TEF anomaly type 1) in both groups. Fifty percent of EE patients had a
811 Table 1
Differences between EE and IE EE
IE
Median age at diagnosis of EE/IE (range) History:
9 y 8 mo 11 y 2 mo (4 y-13 y 4 mo) (8 y 7 mo-15 y 10 mo) 25% Environmental/ 75% seasonal allergies Food allergies 75% 0% Food allergies 0% 50%
Family history: 50% Endoscopy: Difficulty passing endoscope Eosinophilia 100% Blood work: Eosinophilic 75%/25% count 0.5-1/N1
0%
33% 0%/100%
Table represents a selection of the most significant results.
history of prematurity compared with only 1 patient in the IE group. Associated anomalies included the full spectrum of the VACTERL syndrome. The IE group had more associated malformations than the EE group.
2.2. Presenting symptoms Dysphagia was universal in both groups. Dysphagia to solids was seen in 75% of cases. Vomiting was a predominant symptom in 50% of the patients in the EE group, whereas only 1 patient in the IE group had significant vomiting. In both groups, failure to thrive was present in 25% of the patients. Chest pain was more often found in the IE group (EE, 25%; IE, 50%). Constipation and epigastric pain were only present in the IE group (50% and 25%, respectively). Virtually all patients of either group had an atopic condition. Asthma was found in 75% of the patients of both groups, whereas environmental and seasonal allergies were predominant in the EE group (75% and 25%). One patient in the EE group had eczema. Interestingly, food allergies were exclusively seen in the EE group (75%). Furthermore, all patients had GERD as an infant or later. Strictures necessitating dilation were present in 50% of the EE patients vs 25% of the IE patients. A family history of atopy was present universally. Family history of food allergies was not demonstrated in any of the patients in the EE group, whereas such 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 compared with 25% of the IE group. Interestingly, a peripheral eosinophilia was found in all patients of the EE group, with an eosinophilic count of 0.5 to 1 in 3 patients and N1 in 1 patient. One patient of the IE group had a peripheral eosinophilia with a total eosinophilic count of N1.
812 Table 2
C. Oliveira et al. Findings on endoscopy and biopsy
Endoscopy:
Biopsy:
Difficulty passing endoscope Normal esophageal mucosa Esophageal furrows White plaques in the esophagus Pale appearance of the esophagus Hiatus hernia Gastritis Duodenitis Eeosinophilic abscess Degranulated surface eosinophils Elongated reti papillae Gastritis Duodenitis H pylori GERD findings
EE
IE
50% 0% 75% 50% 25% 0% 25% 25% 25% 50% 50% 50% 25% 0% 75%
0% 25% 66% 33% 0% 25% 25% 0% 0% 0% 25% 75% 0% 0% 75%
Barium swallows were abnormal in all subjects. Seventyfive percent of EE patients and 50% of the IE patients had dysmotility, and only 1 EE patient had a mild stricture. The 24-hour pH probe was abnormal in all IE patients and in 75% of EE patients, with an accentuation of the pathologic findings in the IE group. All patients in our series underwent a diagnostic endoscopy. Fifty percent of EE patients needed a smaller endoscope than what would be normally expected. This was not the case in the IE group. Only 1 patient had a normal mucosa of the esophagus on endoscopy (IE patient). The endoscopic findings of our patients are consistent with those described 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 pale appearance (EE, 25%). One patient had a hiatal hernia (IE patient). Nonspecific mucosal changes of the stomach were found in 25% of both groups. The duodenum was abnormal on endoscopy in 1 patient of the EE group (Table 2). On biopsy, more than 20 eosinophils were seen in the lower and middle esophagus in EE patients. One EE patient had less than 5 eosinophils in the upper esophagus. In contrast, IE patients had less eosinophils all over the esophagus. Almost all patients had basal cell hyperplasia, and no patients had ruptured eosinophils. Degranulated surface eosinophils (50%) and eosinophilic abscess (25%) were only found in the EE group. Elongated reti papillae were more often present in EE biopsies (50%) than in IE biopsies (25%). Remarkably, none of the 8 patients was positive for Helicobacter pylori. Eosinophils were found in 1 duodenal biopsy of an EE patient.
2.4. Treatment Proton pump inhibitors were effective in 2 of 3 EE patients and in 75% of IE patients. H2 blockers reduced
symptoms in 1 of 2 EE patients. Prokinetic agents had no effect on the symptoms of our patients. Steroids were the only effective treatment modality. The local (swallowed inhalation steroids) or systemic application of steroids led to complete resolution of symptoms in all patients. A reduction of symptoms was achieved with montelukast (EE, 4/4; IE, 1/1). However, most of 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 their treatment.
3. Discussion To the best of our knowledge, there have been no other reports of EE in the setting of TEF in the surgical literature. The TEF patients as a group have a high incidence of associated GERD, which causes significant long-term morbidity [1]. In a significant minority of the patients, GERD-like symptoms fail to subside despite maximal therapy. One consideration in TEF patients with refractory GERD should be eosinophilic disease. In this study, we compared patients with EE with those with IE, both of which are relatively new diagnostic disease entities. The initial presentation, workup, and endoscopic and histologic findings were also compared. The chronic inflammation caused by GERD is usually restricted to the mucosa of the esophagus, whereas inflammation caused by EE affects all 3 layers [3]. Therefore, a higher rate of stricture formation and dysmotility in EE would be expected compared with GERD. Symptoms of GERD, such as heartburn, chest and epigastric pain, and water brash, were of secondary importance in making the diagnosis of EE, but prevalent in the IE group. This may reflect the less important role of GERD in EE compared with IE. However, an incomplete resolution and persistence of symptoms despite medical and surgical antireflux therapy should raise a suspicion for EE [7]. The incidence of EE in children with GERD refractory to antireflux treatment has been described as 8% to 10% [3]. The previously documented high incidence of atopy in EE patients was in keeping with our findings. Asthma represented the most common atopic condition (75%). Interestingly, food allergies were only found in the EE group, which may imply a stronger impact of food allergies on the pathogenesis of EE compared with IE. All of our patients had a history of GERD, but it remains unclear whether GERD is crucial for the pathogenesis of EE or not. Family history of EE patients is usually positive for atopic diseases 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 a family history of strictures or EE. Although the pathogenesis of EE is not fully understood, there is good evidence to
EE and IE after tracheoesophageal fistula repair support a theory implicating IgE-mediated and T-cell–driven allergic reactions against food and seasonal allergens being crucial for the development of EE [9-11]. Food allergies in particular are thought to induce and exacerbate EE [2,6,7,9,12]. Milk, egg, wheat, and soy are the most common allergens related to EE [13-15]. Because the origin of EE is thought to be—at least in part—of atopic nature, skin prick test and atopic patch test are sometimes of diagnostic value [7,14]. However, the predictive value of both tests shows great variability [7,9,13,14]. The difference in prevalence of peripheral eosinophilia of both groups (EE, 100% vs IE, 25%) supports the theory of IE being a less distinctive form of EE. It is important to note that biopsy is crucial for the diagnosis of EE and IE [3,5,9,14]. Furthermore, it is crucial for a proper diagnosis of EE to take biopsies from widespread locations because EE is described as a patchy disease process [8]. The most important criterion is the presence of eosinophils, which are normally absent in the esophagus [5,7,14]. Twenty or more eosinophils per HPF in the squamous mucosa indicate EE [5,6,13,14]. Another classification accepts N15 eosinophils per HPF as being consistent with EE, 3 to 15 eosinophils with IE, and b3 eosinophils with GERD [3]. Additional feature for the differentiation between EE and GERD is the extent of basal layer hyperplasia [13,16]. No significant difference in the presence of basal layer hyperplasia was noted between the 2 groups in our series. Although EE is usually distributed equally throughout the esophagus, our EE patients showed an accentuation of eosinophils to the lower and mid esophagus, which is typical of GERD [3,8]. Activated mucosal mast cells can be found in addition to the eosinophils [2,11]. In our study population, in addition to the number of eosinophils, discriminating histologic findings between the 2 groups were degranulated surface eosinophils and eosinophilic abscess with predominance in the EE group. Helicobacter pylori, which is responsible for inducing gastritis and duodenitis, was not present in any of the biopsy specimens. Nevertheless, nonspecific gastritis was present in some patients. A correlation between EE and eosinophilic gastritis/duodenitis has been described before [10]. Further biopsies need to be done to follow a possible progression of IE into EE and to define the natural history of this new entity. Treatment options for EE are elemental and elimination diets, and systemic or local steroids [5,6,14,17]. Agents such as montelukast (leukotriene antagonist), cromolyn (mast cell stabilizer), and mepolizumab (anti–interleukin-5) may play an increasing role in the management of EE [3-6]. Leukotriene, interleukin-5, and mast cells are crucial in the IgE-induced allergic reaction. Preventing their action is a reasonable strategy of therapy for an allergic reaction in the esophagus. Aggressive antireflux treatment leads to an improvement of the symptoms in EE, but not to a reduction of the histologic findings [3]. Elemental diets are known to
813 resolve clinical as well as histologic findings in 95% of cases [14]. However, as would be expected, compliance is poor especially in older children [14]. Alternatively, elimination diets with elimination of allergens confirmed by skin prick test and atopic patch test can be applied and may resolve histologic findings in up to 75% of cases [14]. Local steroids lead to resolution of the symptoms in 75% and to a remission of histologic findings in 50% of cases [3,5,17]. Patients with strong association to atopy are less responsive to topical steroids than others [7,17]. Generally, systemic steroids resolve EE during the period of intake; but 35% relapse after withdrawal [5]. Our patients responded to steroids with a reduction of symptoms, but further biopsies and follow-up need to be done to describe the histologic effects and the occurrence of relapses. In conclusion, TEF patients have a high incidence of GERD. Male patients of this group with persistent GERD refractory to maximal medical and surgical therapy or with dysphagia should undergo a diagnostic endoscopy with biopsies to exclude EE or IE. In particular, this is strongly recommended in patients with food or environmental/ seasonal allergies or asthma. Data are needed to define the natural history of IE in TEF patients.
References [1] Little DC, Rescorla FJ, Grosfeld JL, et al. Long-term analysis of children with esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003;38(6):852-6. [2] Kirsch R, Bokhary R, Marcon MA, et al. Activated mucosal mast cells differentiate eosinophilic (allergic) esophagitis from gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007;44(1):20-6. [3] Liacouras CA, Ruchelli E. Eosinophilic esophagitis. Curr Opin Pediatr 2004;16(5):560-6. [4] Batres LA, Liacouras C, Schnaufer L, et al. Eosinophilic esophagitis associated with anastomotic strictures after esophageal atresia repair. J Pediatr Gastroenterol Nutr 2002;35(2):224-6. [5] Ferguson DD, Foxx-Orenstein AE. Eosinophilic esophagitis: an update. Dis Esophagus 2007;20(1):2-8. [6] Furuta GT, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther 2006;24(2):173-82. [7] Markowitz JE, Liacouras CA. Eosinophilic esophagitis. Gastroenterol Clin North Am 2003;32(3):949-66. [8] Blanchard C, Wang N, Rothenberg ME. Eosinophilic esophagitis: pathogenesis, genetics, and therapy. J Allergy Clin Immunol 2006;118 (5):1054-9. [9] Pentiuk SP, Miller CK, Kaul A. Eosinophilic esophagitis in infants and toddlers. Dysphagia 2007;22(1):44-8. [10] Mishra A, Schlotman J, Wang M, et al. Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J Leukoc Biol 2007;81(4):916-24. [11] Straumann A, Spichtin HP, Grize L, et al. Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 2003;125(6):1660-9. [12] Liacouras CA, Markowitz JE. Predictors of early recurrence of benign esophageal strictures: what about eosinophilic esophagitis? Am J Gastroenterol 2004;99(1):182-3. [13] Kakakios A, Heine RG. Eosinophilic oesophagitis. Med J Aust 2006;185(7):401.
814 [14] Spergel JM, Brown-Whitehorn T, Beausoleil JL, et al. Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis. J Allergy Clin Immunol 2007;119(2):509-11. [15] Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol 2007;119 (1):206-12.
C. Oliveira et al. [16] Steiner SJ, Kernek KM, Fitzgerald JF. Severity of basal cell hyperplasia differs in reflux versus eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2006;42(5):506-9. [17] Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, doubleblind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology 2006;131(5):1381-91.
