Diseases of the Esophagus (2015) ••, ••–•• DOI: 10.1111/dote.12368
Original article
Treatment outcomes for eosinophilic esophagitis in children with esophageal atresia L. J. Chan, L. Tan, J. Dhaliwal, F. Briglia, C. Clarkson, U. Krishnan Department of Paediatric Gastroenterology, Sydney Children’s Hospital, University of New South Wales, Sydney, New South Wales, Australia
SUMMARY. Eosinophilic esophagitis (EoE) has been reported to be more prevalent in patients with esophageal atresia/tracheoesophageal fistula (EA-TEF). To date, there is limited data on the management of EoE in this group of patients. The aim of this study is to evaluate the treatment outcomes of EoE in children with EA-TEF. A retrospective chart review was performed on all EA-TEF children who were diagnosed with and treated for EoE between January 2000 and September 2013 at the Sydney Children’s Hospital. Data collected included details of the patient’s treatment, post-treatment endoscopy, symptoms and nutrition. Twenty patients were included in the study. Median age at diagnosis was 26 months (8–103 months), and median time from diagnosis to last follow-up was 23 months (2–132 months). Patients were treated with budesonide slurry, swallowed fluticasone, elimination diet alone or in combination. All patients were on proton pump inhibitors at time of diagnosis of EoE which was continued. Six out of seven patients who had furrowing/exudate in endoscopy at diagnosis had complete resolution at a median follow-up period of 26 months (P = 0.031). Median peak intraepithelial eosinophil count reduced significantly from 30/high-powered field (HPF) (19–80/HPF) to 8/HPF (0–85/HPF) (median time for improvement = 24 months) (P = 0.015). There was a significant reduction in symptoms of dysphagia and reflux post-treatment (P < 0.001). Prevalence of strictures significantly decreased (P = 0.016), as did need for dilatations (P = 0.004). In four out of six patients with gastrostomies at baseline, the feeding improved on treatment of EoE and the gastrostomy could be closed. There was also a nonsignificant trend towards improvement in weight and height ‘z scores’ of the patients. Treatment of EoE in children with EA-TEF was found to significantly reduce intraepithelial eosinophil count, symptoms, strictures and need for dilatations. KEY WORDS: child, eosinophilic esophagitis, esophageal atresia, tracheoesophageal atresia.
INTRODUCTION Eosinophilic esophagitis (EoE) is a chronic disease of the esophagus and is characterized by esophageal dysfunction and eosinophil-predominant inflammation of ≥15 eosinophils per high-powered field (HPF).1 Treatment in the pediatric population usually comprises of either topical steroids, dietary modification or a combination of both. As EoE has recently been recognized as a condition distinct from other esophageal pathologies (e.g. gastroesophageal reflux disease [GERD]), management and assessment of potential long-term complications has been Address correspondence to: Dr Usha Krishnan, MBBS, FRACP, Department of Paediatric Gastroenterology, Level 4, Emergency Wing, Sydney Children’s Hospital, High Street, Randwick, NSW 2031, Australia. Email: [email protected] © 2015 International Society for Diseases of the Esophagus
challenging. Response to treatment of EoE in the general population results in improvement of symptoms such as dysphagia and feeding difficulties especially in children.2 A greater prevalence of EoE in patients born with esophageal atresia (EA) and tracheoesophageal fistula (TEF) has been recently described.3–5 Diagnosing EoE in patients with esophageal atresia/ tracheoesophageal fistula (EA-TEF) is difficult, because of the inherent esophageal dysmotility and presence of GERD in this cohort, with symptoms of both being similar to that of EoE. Feeding difficulties, severe GERD, recurrent anastomotic strictures and dysphagia are common in TEF patients regardless of whether EoE has been diagnosed.6 There is limited data on the management of EoE in the EA-TEF cohort. In our study, we aim to add to the current understanding of EoE treatment in 1
2
Diseases of the Esophagus
children with EA-TEF by examining treatment outcomes of EoE in children with EA-TEF.
METHODS Selection criteria This was an observational, descriptive and monocentric study. A detailed retrospective chart review was performed on all EA-TEF children who were diagnosed with and treated for EoE between January 2000 and September 2013 at Sydney Children’s Hospital, Australia. Of 113 EA-TEF patients during this period, 24 patients were diagnosed with EoE. Four patients were excluded as they were lost to follow–up, and there was insufficient data to determine treatment outcomes. A total of 20 patients were included in our study. Inclusion criteria were: (i) a diagnosis of EoE was based on at least one baseline esophageal biopsy demonstrating a peak eosinophil count ≥15/HPF;1 (ii) use of proton pump inhibitor (PPI) prior to diagnosis of EoE and at time of diagnosis of EoE; and (iii) patients must also have had documented endoscopies and biopsies performed at baseline diagnosis and subsequent follow up.7
annually was calculated, both pre-diagnosis and during treatment of EoE. Baseline results were calculated at diagnosis of EoE as follows:Number of strictures requiring dilatations/patient’s age (years). Post-treatment results: Number of esophageal strictures requiring dilatation from time of treatment for EoE to last follow-up date/number of years between the two time points. Gastrostomy
Information was collected on the number of new gastrostomies inserted after the diagnosis of EoE and whether any gastrostomies which had been placed prior to the diagnosis of EoE due to feeding difficulties were closed after treatment. Symptoms
Details of self-reported or parental reported symptoms were noted. These included dysphagia, reflux symptoms, dying spells and food bolus impaction requiring endoscopic removal. Growth and nutrition
Effects of EoE treatment on growth were monitored, as determined by the weight and height z-scores at baseline (EoE diagnosis) and most recent follow-up.
Studied outcomes were Endoscopic and histological changes in esophageal biopsies
At each endoscopy, macroscopic appearances suggestive of EoE such as longitudinal furrowing, exudates and esophageal thickening were recorded. Four to six biopsies per patient were collected from both proximal and distal esophagus at baseline and follow-up endoscopy. The number of biopsies recommended by current guidelines is at least two to four specimens of the proximal and distal esophagus and with six biopsy specimens yielding 100% diagnostic sensitivity.1,7,8 Studied histological parameters were peak eosinophil count/high powered field (eos/hpf) and chronic reactive changes such as basal cell hyperplasia, lamina propria elongation, spongiosis, parakeratosis and subepithelial hyalinization. Esophageal strictures requiring dilatation
A stricture was defined as >50% decrease in diameter of the lumen of the esophagus, with holdup of contrast above the level of the stricture and dilatation of the esophagus seen above the level of the stricture in the presence of symptoms in patients who subsequently need dilatation of their strictures for relief of symptoms. The number of esophageal dilatations for strictures pre- and post-treatment of EoE was evaluated. The number of dilatations that a patient required
Statistical analysis All statistical analysis was performed using IBM SPSS Statistics 20 for Windows (Armonk, NY, USA). Continuous data were analyzed using paired t-test or Wilcoxon test, while Chi-square test and McNemar test were used for categorical and dichotomous variables, respectively. Statistical significance was assumed with P-value 2 vertebral bodies between the two esophageal pouches © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia Table 1 Baseline characteristics of patients (n = 20) Prevalence (%) Median (range) Gender Male 12 (60) Female 8 (40) Gestation (weeks) Age at diagnosis (months) Type of EA Proximal EA with distal TEF 16 (80) Isolated EA 2 (10) Isolated TEF 2 (10) Long-gap EA-TEF 5 (25) Associated anomalies VACTERL association 2 (10) CHARGE association 1 (5) Vertebral anomalies only 1 (5) Cardiac anomalies only 1 (5)
3
Eight patients were tested positive with egg, peanut and milk as the most common allergies. Treatment
37 (28–40) 26 (8–103)
EA-TEF, esophageal atresia/tracheoesophageal fistula; CHARGE, coloboma, heart defect, atresia choanae, retarded growth and development, genital and ear abnormalities; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies and limb abnormalities.
is defined as long-gap EA), and two of the 5 LGEA patients were repaired by Foker procedure9 (refer to Table 1). Five patients had been fundoplicated in the past for GERD prior to their diagnosis of EoE. Only one of these was a LGEA. Both the LGEA who were repaired using Foker technique had not been fundoplicated as their reflux was well controlled on medical therapy. Of the 20 patients, 14 (70%) had a history of atopy. The most prevalent form of allergy was asthma, followed by food allergy and eczema (Table 2). Information on family history of atopy was collected in eight patients, positive in seven patients, commonest being history of asthma, rhinitis and eczema. Food allergy testing was conducted on 14 patients. Nine had both skin-prick tests (SPT) and radioallergosorbent test (RAST), four had only SPT, and one had only RAST. At our centre, a standardized panel for SPT was developed specially for EoE patients which consists of common allergens from major food groups (whole milk, egg white, peanut, soya, cashew, rye flour, rice, oats, corn, wheat, chicken, beef, cod, shrimp). For RAST, allergens that were frequently ordered consisted of dairy, nuts/ peanut, egg, wheat, soy, fish/shellfish and rice. Positive RAST results were always confirmed by SPT.
EoE was treated with either viscous budesonide slurry (n = 8), swallowed fluticasone (n = 5), elimination diet (targeted based on results of SPT or six food elimination diet or elemental amino acid based formula) (n = 1) or a combination of these therapies (n = 6).1,7,8 Budesonide slurry was dosed at 0.5–1.0 mg twice daily and swallowed fluticasone at 50–500 mcg taken as two puffs twice daily, depending on the age of the patients. Treatment with topical swallowed steroids was well tolerated with no adverse effects observed. Based on the results of RAST and SPT, targeted foods were also eliminated from diet if there were any positive results. The six-food elimination diet or elemental formula was used only in patients with poor response to targeted food elimination or with medication alone. Two patients were on elemental formula. One of them had severe eczema and was on six food elimination and targeted food elimination diet in addition to an elemental amino acid based formula. The other patient was treated with amino acid-based formula for 8 weeks following poor response of the EoE on a repeat endoscopy to budesonide slurry in combination with targeted food elimination diet. At the time of diagnosis of EoE, all patients were also on PPIs for GERD. This was continued throughout the treatment period in addition to EoE-specific therapy. PPI therapy was administered at a standard dose of at least 1 mg/kg/dose, once or twice daily. Endoscopic appearance Endoscopy reports at baseline, and final follow-up were reviewed. Seven out of 20 patients (35%) had a typical endoscopic evidence of EoE in the form of longitudinal furrowing and/or white exudates (Fig. 1). At follow-up endoscopy, six out of seven (86%) patients had normal endoscopic appearance, at a median follow-up period of 26 months, with resolution of the furrowing and exudates (P = 0.031). The one patient in whom the furrowing persisted was poorly compliant to EoE treatment. Strictures
Table 2 Results of allergy testing in study group Types of allergy
Number of patients (%)
Positive atopic history 1 type of atopic disease ≥2 atopic diseases Asthma Food allergy Eczema Rhinitis
14 (70) 6 (30) 8 (40) 11 (55) 8 (40) 6 (30) 1 (5)
© 2015 International Society for Diseases of the Esophagus
Eight out of 20 (40%) patients had strictures at baseline endoscopy at time of diagnosis of EoE (Fig. 2a and 2b). Six out of eight patients were treated with endoscopic balloon dilatations at time of diagnosis of EoE. In the other two, the luminal diameter of the esophagus at the level of previously documented stricture improved on progress endoscopy, in association with improvement in symptoms on medical treatment of EoE with topical swallowed budesonide
4
Diseases of the Esophagus
(a)
of EoE annually was 1.9 (Fig. 3b). Post-treatment of EoE, three of these 12 patients (P = 0.004) developed new strictures which required further dilatations to improve luminal diameter at site of strictures resulting in symptomatic improvement, with a mean of 0.9 dilatation per patient annually (P = 0.005). Histology Intraepithelial eosinophil count
Eosinophil counts per high-powered field were reduced at follow-up biopsies in 17 of 20 patients
(b)
Fig. 1 Pretreatment endoscopic evidence of EoE in EA-TEF patient. (a) Longitudinal furrowing. (b) White exudate.
slurry alone without need for dilatation. Figure 2b shows a stricture with narrowing of the esophageal lumen at time of initial diagnosis of EoE. After medical treatment of EoE, there was an improvement in the luminal diameter of the esophagus at the site of the previously documented stricture as shown in Figure 2c in the same patient. Due to this improvement in the luminal diameter on medical treatment of EoE, an appropriately sized endoscope was able to traverse the stricture in this patient. The locations of strictures were documented in seven patients, and in six of seven, the stricture was at the site of EA repair/ anastomosis. In follow-up endoscopy at a median of 28 months (range 23–132), only one patient was found to have stricture (P = 0.016) and which was endoscopically dilated. Patients who did not present with strictures at baseline did not develop strictures subsequently (Fig. 3a). Esophageal dilatation Twelve patients had strictures requiring at least one dilatation prior to EoE diagnosis and treatment. The mean number of dilatations per patient pre-diagnosis
Fig. 2 (a) Barium swallow of a symptomatic EoE stricture in EA-TEF patient. (b) Pretreatment EoE stricture in a EA-TEF patient. (c) Post-treatment endoscopic improvement of esophageal stricture with medical treatment alone in the same patient. © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
5
(a)
(b)
Fig. 3 (a) Number of patients with strictures at baseline and follow-up endoscopies (P = 0.016). (b) Number of dilatations per patient annually at baseline and at follow-up (P = 0.005).
(Fig. 5a and 5b). Peak intraepithelial eosinophil count was significantly reduced from a median of 30/HPF (range 19–80/HPF) at baseline to 8/HPF (range 0–85/HPF) at follow-up biopsies (P = 0.015) (Fig. 4). Median eosinophil count in the proximal esophageal biopsies reduced from 19 to 0 (P = 0.123), and those in the distal esophageal biopsies reduced from 30 to 10 (P = 0.013) Figure 5 shows an improve-
Fig. 5 (a) Pretreatment histological slide of EA-TEF patient with EoE showing an increase in intraepithelial eosinophils. (b) Post-treatment slide of the same EA-TEF patient showing histological improvement with reduction in the number of intraepithelial eosinophils.
ment in the esophageal histology with reduced eosinophil numbers post treatment of EoE. Median time between baseline and follow-up biopsies was 24 months (2–132 months). When the patients were categorized according to the type of treatment received for EoE, there was a reduction in peak eosinophil count irrespective of the type of EoE treatment (Fig. 6), although it was only in those patients who received a combination therapy of diet and swallowed steroids was there a significant reduction in the peak eosinophil count (P = 0.001). Other histological changes
Fig. 4 Peak intraepithelial eosinophil count at baseline and post-treatment biopsies (P = 0.015). © 2015 International Society for Diseases of the Esophagus
Reactive changes associated with EoE were compared at baseline and at follow-up biopsies. All patients had at least one of the three forms of reactive changes at baseline. Eight (40%) patients had subepithelial hyalinization, 17 (85%) had spongiosis, 19 (95%) had basal cell hyperplasia, and 19 (95%) had lamina propria elongation, and 9/17 (53%) were noted to have parakeratosis at baseline. After treatment, four of eight (50%) patients had complete resolution of hyalinization. There was also a significant
6
Diseases of the Esophagus
Fig. 6 Peak intraepithelial eosinophil count at baseline and follow-up biopsies with different treatment modalities.
Fig. 8 Number of symptomatic patients at baseline and at follow-up.
reduction in the severity of spongiosis, basal cell hyperplasia, lamina propria elongation and parakeratosis were reported in 11/17 (65%), 12/19 (63%), 13/19 (68%) and 6/9 (67%) patients, respectively (Fig. 7).
toms improved after therapy (P < 0.001). No child had food bolus impaction requiring endoscopic removal post-EoE treatment. Two patients experienced ‘dying/cyanotic spells’ pretreatment of EoE. Post-treatment of EoE, these patients no longer experienced these spells (Fig. 8).
Gastrostomy
Growth and nutrition
At time of diagnosis of EoE, there were six patients who had gastrostomy in situ. Post EoE treatment, four patients had closures of their gastrostomy within 12 months (P = 0.125). In two patients, a gastrostomy was inserted during the course of EoE treatment. One patient had it inserted due to the presence of a laryngeal cleft, to improve nutrition and help with administration of the elemental formula. Subsequent to the repair of the laryngeal cleft and improvement of EoE on elemental formula, an oral diet has been reintroduced. In the other patient, the gastrostomy was inserted to help improve nutrition. Symptoms
Dysphagia was seen in 80% and food bolus impaction was seen in 5% of our patients at baseline at time of diagnosis of EoE. Seventy-five percent also reported reflux symptoms. Both dysphagia and reflux symp-
Fig. 7 Number of patients with reactive changes at baseline and at follow-up.
The growth of patients was determined by their ageadjusted weight and height z-scores. Mean weight z-score improved from −1.28 to −0.89 (P = 0.156). Thirteen patients had paired height measurements recorded at baseline and follow-up. The mean height z-score improved from −0.92 to −0.80 (P = 0.558).
DISCUSSION Eosinophilic esophagitis is a condition that is becoming increasingly recognized as a distinct disease entity from other esophageal eosinophilia conditions such as reflux esophagitis.10 The prevalence of EoE in the children is reported to be at 0.89 to 4.30 per 10 000 children in different countries.11–13 Recently, there were reports demonstrating a greater prevalence of EoE in patients with EA-TEF as compared to the general pediatric population.3–5 Prevalence of EoE was reported to be at 17% and 1 in 80 in children with EA-TEF.3,14 There are several hypotheses to explain the increased prevalence of EoE in patients with EA-TEF. Esophageal dysmotility as a result of EA-TEF repair could prolong contact between food antigens and esophageal mucosa, predisposing to EoE.15 In addition, long-term follow-up studies have demonstrated that chronic GERD is prevalent in 35% to 58% patients long after EA-TEF repair.6,16 When chronically exposed to acid, the esophageal mucosa becomes permeable to small peptides up to 20 kd that would normally be impermeable in normal esophageal mucosa, which could potentially result in sensitization of food allergens in deeper layer of the © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
esophagus.17 Due to chronic GERD, EA-TEF patients are often put on long-term PPI therapy. This early and prolonged exposure to PPI could prevent breaking down of food antigens thereby increasing the potential for sensitization to certain food antigens which may lead to the development of EoE.18 Genetic similarities between EA-TEF and EoE have also been reported.14 Despite the greater prevalence of EoE in EA-TEF patients as well as the genetic and pathophysiological associations between these two diseases, there is a possibility that EoE could have developed separately from EA-TEF and the responses of the EA-TEF patients to standard EoE treatment may not be of any different from non-EA-TEF patients with EoE. The first comprehensive diagnostic and management consensus recommendations for EoE was first published in 2007.19 Subsequently, several other papers had been published including the updated consensus recommendation and the American College of Gastroenterology Clinical Guidelines.1,7,8 These consensus recommendations agreed on using the three main management options for EoE – medications (budesonide slurry and swallowed fluticasone), dietary (elemental, empirical and targeted elimination diets) and esophageal dilatations. Our study is the first to investigate the treatment outcomes of EoE in EA-TEF children. The EoE treatment that our study group received was consistent with current recommendations. In our institution, topical steroids are prescribed as an initial therapy for EoE either in the form of budesonide slurry or swallowed fluticasone. Dietary elimination therapy is reserved for those patients who fail to improve clinically and histologically with topical steroids. EA-TEF children often concurrently have significant feeding difficulties, failure to thrive and GERD, and these families find the addition of a restrictive diet often too difficult to comply with. No patients required the use of systemic steroids in this study. Esophageal dilatations were reserved for symptomatic patients who have persisting strictures despite pharmacological and dietary therapy for their EoE. Our study is the first to demonstrate that the treatment of EoE in children with EA-TEF not only significantly reduces intraepithelial eosinophil count and reactive changes associated with EoE, but it also significantly reduces stricture occurrence and improves dysphagia and reflux symptoms. The intraepithelial eosinophil count was significantly reduced in 17 patients, particularly with the combination of topical steroids and elimination diet. The other three patients who had an increase in intraepithelial eosinophil count were noncompliant to treatment. The incidence of strictures significantly reduced post-treatment of EoE and the number of dilata© 2015 International Society for Diseases of the Esophagus
7
tions required per patient annually was also significantly reduced. None of our patients required endoscopic removal of food bolus impaction posttreatment, reflecting an improvement in the stricture incidence. As strictures are common in EA-TEF patients,20 our study highlights the importance of excluding EoE in EA-TEF patients with recurrent strictures and not proceeding fundoplication routinely in these patients, as not only GERD but also EoE can result in recurrent strictures. The improvement in strictures in two patients on treatment of EoE alone without need for endoscopic dilatation also underlines the absolute need for endoscopy with biopsies prior to dilatation of strictures in EA-TEF patients with recurrent strictures and increasing dysphagia. We feel that the ability of an age appropriate endoscope to traverse the esophagus due to an improvement in the luminal diameter at the site of a previously documented stricture after medical therapy of EoE could be used as an objective parameter to support the effectiveness of the medical therapy of EoE in patients with strictures secondary to EoE in addition to an improvement in the histology. Post EoE treatment, gastrostomy closures were performed on four of six patients, suggesting EoE may have been contributing to the feeding difficulties. However, given the small number of patients, it is difficult to determine the efficacy of EoE treatment on feeding improvement and weaning from gastrostomy feeds. A larger prospective study would be required to establish this association. We feel that our results highlight the importance of excluding not only GERD but also EoE in EA-TEF patients with feeding difficulties and failure to thrive in order to avoid further unnecessary surgical interventions. In our study, there was trend towards a nonsignificant improvement in weight and height z-scores in patients’ post-treatment of their EoE. The lack of significance could have been due to the small numbers, the fact that the follow-up was not of the same duration in all patients and that in EA-TEF patients there could be other causes for poor weight gain.6 This also highlights the need for long-term follow-up studies on treatment in EA-TEF patients with EoE. There was a significant symptomatic improvement in dysphagia and reflux symptoms, both of which were the most common complaints in the EA-TEF cohort.21 This symptomatic improvement could be due to the reduced inflammation leading to improved esophageal motility and clearance of refluxate. Interestingly, the two patients who reported ‘hypoxic/ cyanotic spells’ pretreatment of EoE had no further episodes post-treatment. The etiology of these spells in the EA-TEF is thought to be multifactorial with esophageal dysmotility, GERD, strictures and tracheomalacia all thought to play a role.22 We
8
Diseases of the Esophagus
hypothesize that EoE treatment, by improving esophageal motility, clearance of refluxate and reducing stricture incidence, could potentially lead to a reduction in the incidence of these ‘hypoxic/cyanotic spells’. We therefore feel that it is important to exclude EoE in EA-TEF patients with “hypoxic/ cyanotic spells” before proceeding to aortopexy or fundoplication which are the standard treatment options for this condition. We acknowledge that our study had only small number of patients, and larger prospective trials will be needed to confirm our findings. In addition, as the natural history of EA-TEF is not well defined, prior esophageal dilatations may have impacted on subsequent clinical symptoms and need for repeated dilatations. Therefore, there is possibility that the improved outcomes may not have been directly related solely to EoE therapy alone. Of the four patients who had fundoplication at baseline, the mean time from fundoplication to the diagnosis of EoE was 23 months (range 20–25 months). It is difficult to determine whether patients who underwent fundoplication prior to the diagnosis of EoE were symptomatic at the time of their surgery as a result of severe reflux symptoms or undiagnosed EoE or both. The similarity of symptoms observed in GERD and EoE makes it difficult to differentiate between both in the absence of endoscopy and biopsy and pH monitoring. However, given the significant improvement in reflux symptoms post-EoE treatment, we feel that it is important to exclude EoE with an endoscopy and biopsy prior to considering fundoplication in EA-TEF patients with persistent symptoms on medical treatment for their GERD symptoms. There have been reports in literature of PPIresponsive eosinophilia but we feel that our cohort represents true EoE rather than this condition as all our patients were on standard doses of PPI at baseline at the time of diagnosis of their EoE. However, we agree with the consensus guidelines on EoE published earlier1,7,8 that if ≥15 eosinophils/HPF are seen on biopsy in patient not on PPI, then as a first step, these patients should be initially trialed on PPI in standard doses and then have a repeat endoscopy and biopsy. If there is persistent eosinophilia of ≥15 eos/HPF, only then should they proceed to standard EoE treatment. This is especially important in the EA-TEF cohort who has a high incidence of GERD.6,16 Improvement in histology, endoscopy and symptoms has been reported in several studies that investigated the use of oral steroids and elimination diet in children with EoE.23,24 However, relapses were observed once treatments were stopped. A retrospective study by Liacouras et al. reported that 50% of patients have recurrence of symptoms and worsening histology at 12 months post cessation of treatment despite initial improvement or resolution of symp-
toms post-treatment.25 Similarly in Schaefer et al.’s study, the participants received a 4-week treatment followed by 8 weeks weaning protocol had histological and symptomatic improvement at 4 weeks, but 45% of the participants relapsed at 24 weeks.26 In our study, two patients discontinued treatment after 77 and 8 months of treatment with elimination diet and swallowed fluticasone, respectively, and 15 months later there is no sign of relapse clinically or histopathologically. However in two other patients who were noncompliant to treatment did experience clinical and histopathological recurrence and treatment reinitiated. This shows the importance of maintenance therapy in EoE even after inducing remission in order to avoid relapses. Long-term follow-up studies would be needed to determine the optimal duration of treatment to maintain remission of EoE. In conclusion, our study has shown that treating EoE in children with EA-TEF leads to not only mucosal healing but also results in a significant improvement in clinical symptoms, stricture recurrence and the subsequent need for dilatations. We feel that the results of this study underline the importance and absolute need for endoscopic biopsy at the time of stricture dilatation in EA-TEF patients. We also recommend endoscopy with biopsies in EA-TEF patients with increasing dysphagia, recurrent strictures, feeding difficulties being considered for gastrostomy placement and particularly in those with persistent symptoms on PPI prior to consideration for surgical procedures such as fundoplication for recurrent strictures. We feel that it is important in the future to do long-term follow-up studies in the cohort of EA-TEF patients with EoE to determine treatment outcomes including effect on growth and nutrition over a longer time period. Our team is currently involved in a prospective study aiming to determine whether there is an improvement in the quality of life of these patients post-treatment of their EoE. References 1 Liacouras C A, Furuta G T, Hirano I et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3–20. 2 Dellon E S. Diagnosis and management of eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012; 10: 1066–78. 3 Dhaliwal J, Tobias V, Sugo E et al. Eosinophilic esophagitis in children with esophageal atresia. Dis Esophagus 2014; 27: 340–7. 4 Batres L A, Liacouras C, Schnaufer L, Mascarenhas M R. Eosinophilic esophagitis associated with anastomotic strictures after esophageal atresia repair. J Pediatr Gastroenterol Nutr 2002; 35: 224–6. 5 Oliveira C, Zamakhshary M, Marcon P, Kim P C. Eosinophilic esophagitis and intermediate esophagitis after tracheoesophageal fistula repair: a case series. J Pediatr Surg 2008; 43: 810–4. 6 Kovesi T, Rubin S. Long-term complications of congenital esophageal atresia and/or tracheoesophageal fistula. Chest 2004; 126: 915–25. 7 Dellon E S, Gonsalves N, Hirano I et al. ACG clinical guideline: evidenced based approach to the diagnosis and manage© 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
8 9 10 11 12 13 14
15
16
17
ment of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013; 108: 679–92. Papadopoulou A, Koletzko S, Heuschkel R et al. Management guidelines of eosinophilic esophagitis in childhood. J Pediatr Gastroenterol Nutr 2014; 58: 107–18. Nasr A, Langer J C. Mechanical traction techniques for longgap esophageal atresia: a critical appraisal. Eur J Pediatr Surg 2013; 23: 191–7. Liacouras C A. Eosinophilic esophagitis in children and adults. J Pediatr Gastroenterol Nutr 2003; 37 (Suppl. 1): S23–8. Noel R J, Putnam P E, Rothenberg M E. Eosinophilic Esophagitis. NEJM 2004; 351: 940–1. Cherian S, Smith N M, Forbes D A. Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia. Arch Dis Child 2006; 91: 1000–4. Furuta G T, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther 2006; 24: 173–82. Gorter R R, Heij H A, van der Voorn J P, Kneepkens C M F. Eosinophilic esophagitis after esophageal atresia: is there an association? Case presentation and literature review. J Pediatr Surg 2012; 47: e9–13. Deurloo J A, Klinkenberg E C, Ekkelkamp S et al. Adults with corrected oesophageal atresia: is oesophageal function associated with complaints and/or quality of life? Pediatr Surg Int 2008; 24: 537–41. Deurloo J A, Ekkelkamp S, Bartelsman J F et al. Gastroesophageal reflux: prevalence in adults older than 28 years after correction of esophageal atresia. Ann Surg 2003; 238: 686–9. Tobey N A, Carson J L, Alkiek R A, Orlando R C. Dilated intercellular spaces: a morphological feature of acid reflux – damaged human esophageal epithelium. Gastroenterology 1996; 111: 1200–5.
© 2015 International Society for Diseases of the Esophagus
9
18 Pali-Schöll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011; 66: 469–77. 19 Furuta G T, Liacouras C A, Collins M H et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342–63. 20 Serhal L, Gottrand F, Sfeir R et al. Anastomotic stricture after surgical repair of esophageal atresia: frequency, risk factors, and efficacy of esophageal bougie dilatations. J Pediatr Surg 2010; 45: 1459–62. 21 Little D C, Rescorla F J, Grosfeld J L et al. Long-term analysis of children with esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003; 38: 852–6. 22 Shah R, Varjavandi V, Krishnan U. Predictive factors for complications in children with esophageal atresia and tracheoesophageal fistula. Dis Esophagus 2014; 28: 216–223. doi: 10.1111/dote.12177 23 Aceves S S, Bastian J F, Newbury R O, Dohil R. Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children. Am J Gastroenterol 2007; 102: 2271–9, quiz 2280. 24 Markowitz J E, Spergel J M, Ruchelli E, Liacouras C A. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol 2003; 98: 777–82. 25 Liacouras C A, Wenner W J, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998; 26: 380–5. 26 Schaefer E T, Fitzgerald J F, Molleston J P et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clin Gastroenterol Hepatol 2008; 6: 165–73.
Original article
Treatment outcomes for eosinophilic esophagitis in children with esophageal atresia L. J. Chan, L. Tan, J. Dhaliwal, F. Briglia, C. Clarkson, U. Krishnan Department of Paediatric Gastroenterology, Sydney Children’s Hospital, University of New South Wales, Sydney, New South Wales, Australia
SUMMARY. Eosinophilic esophagitis (EoE) has been reported to be more prevalent in patients with esophageal atresia/tracheoesophageal fistula (EA-TEF). To date, there is limited data on the management of EoE in this group of patients. The aim of this study is to evaluate the treatment outcomes of EoE in children with EA-TEF. A retrospective chart review was performed on all EA-TEF children who were diagnosed with and treated for EoE between January 2000 and September 2013 at the Sydney Children’s Hospital. Data collected included details of the patient’s treatment, post-treatment endoscopy, symptoms and nutrition. Twenty patients were included in the study. Median age at diagnosis was 26 months (8–103 months), and median time from diagnosis to last follow-up was 23 months (2–132 months). Patients were treated with budesonide slurry, swallowed fluticasone, elimination diet alone or in combination. All patients were on proton pump inhibitors at time of diagnosis of EoE which was continued. Six out of seven patients who had furrowing/exudate in endoscopy at diagnosis had complete resolution at a median follow-up period of 26 months (P = 0.031). Median peak intraepithelial eosinophil count reduced significantly from 30/high-powered field (HPF) (19–80/HPF) to 8/HPF (0–85/HPF) (median time for improvement = 24 months) (P = 0.015). There was a significant reduction in symptoms of dysphagia and reflux post-treatment (P < 0.001). Prevalence of strictures significantly decreased (P = 0.016), as did need for dilatations (P = 0.004). In four out of six patients with gastrostomies at baseline, the feeding improved on treatment of EoE and the gastrostomy could be closed. There was also a nonsignificant trend towards improvement in weight and height ‘z scores’ of the patients. Treatment of EoE in children with EA-TEF was found to significantly reduce intraepithelial eosinophil count, symptoms, strictures and need for dilatations. KEY WORDS: child, eosinophilic esophagitis, esophageal atresia, tracheoesophageal atresia.
INTRODUCTION Eosinophilic esophagitis (EoE) is a chronic disease of the esophagus and is characterized by esophageal dysfunction and eosinophil-predominant inflammation of ≥15 eosinophils per high-powered field (HPF).1 Treatment in the pediatric population usually comprises of either topical steroids, dietary modification or a combination of both. As EoE has recently been recognized as a condition distinct from other esophageal pathologies (e.g. gastroesophageal reflux disease [GERD]), management and assessment of potential long-term complications has been Address correspondence to: Dr Usha Krishnan, MBBS, FRACP, Department of Paediatric Gastroenterology, Level 4, Emergency Wing, Sydney Children’s Hospital, High Street, Randwick, NSW 2031, Australia. Email: [email protected] © 2015 International Society for Diseases of the Esophagus
challenging. Response to treatment of EoE in the general population results in improvement of symptoms such as dysphagia and feeding difficulties especially in children.2 A greater prevalence of EoE in patients born with esophageal atresia (EA) and tracheoesophageal fistula (TEF) has been recently described.3–5 Diagnosing EoE in patients with esophageal atresia/ tracheoesophageal fistula (EA-TEF) is difficult, because of the inherent esophageal dysmotility and presence of GERD in this cohort, with symptoms of both being similar to that of EoE. Feeding difficulties, severe GERD, recurrent anastomotic strictures and dysphagia are common in TEF patients regardless of whether EoE has been diagnosed.6 There is limited data on the management of EoE in the EA-TEF cohort. In our study, we aim to add to the current understanding of EoE treatment in 1
2
Diseases of the Esophagus
children with EA-TEF by examining treatment outcomes of EoE in children with EA-TEF.
METHODS Selection criteria This was an observational, descriptive and monocentric study. A detailed retrospective chart review was performed on all EA-TEF children who were diagnosed with and treated for EoE between January 2000 and September 2013 at Sydney Children’s Hospital, Australia. Of 113 EA-TEF patients during this period, 24 patients were diagnosed with EoE. Four patients were excluded as they were lost to follow–up, and there was insufficient data to determine treatment outcomes. A total of 20 patients were included in our study. Inclusion criteria were: (i) a diagnosis of EoE was based on at least one baseline esophageal biopsy demonstrating a peak eosinophil count ≥15/HPF;1 (ii) use of proton pump inhibitor (PPI) prior to diagnosis of EoE and at time of diagnosis of EoE; and (iii) patients must also have had documented endoscopies and biopsies performed at baseline diagnosis and subsequent follow up.7
annually was calculated, both pre-diagnosis and during treatment of EoE. Baseline results were calculated at diagnosis of EoE as follows:Number of strictures requiring dilatations/patient’s age (years). Post-treatment results: Number of esophageal strictures requiring dilatation from time of treatment for EoE to last follow-up date/number of years between the two time points. Gastrostomy
Information was collected on the number of new gastrostomies inserted after the diagnosis of EoE and whether any gastrostomies which had been placed prior to the diagnosis of EoE due to feeding difficulties were closed after treatment. Symptoms
Details of self-reported or parental reported symptoms were noted. These included dysphagia, reflux symptoms, dying spells and food bolus impaction requiring endoscopic removal. Growth and nutrition
Effects of EoE treatment on growth were monitored, as determined by the weight and height z-scores at baseline (EoE diagnosis) and most recent follow-up.
Studied outcomes were Endoscopic and histological changes in esophageal biopsies
At each endoscopy, macroscopic appearances suggestive of EoE such as longitudinal furrowing, exudates and esophageal thickening were recorded. Four to six biopsies per patient were collected from both proximal and distal esophagus at baseline and follow-up endoscopy. The number of biopsies recommended by current guidelines is at least two to four specimens of the proximal and distal esophagus and with six biopsy specimens yielding 100% diagnostic sensitivity.1,7,8 Studied histological parameters were peak eosinophil count/high powered field (eos/hpf) and chronic reactive changes such as basal cell hyperplasia, lamina propria elongation, spongiosis, parakeratosis and subepithelial hyalinization. Esophageal strictures requiring dilatation
A stricture was defined as >50% decrease in diameter of the lumen of the esophagus, with holdup of contrast above the level of the stricture and dilatation of the esophagus seen above the level of the stricture in the presence of symptoms in patients who subsequently need dilatation of their strictures for relief of symptoms. The number of esophageal dilatations for strictures pre- and post-treatment of EoE was evaluated. The number of dilatations that a patient required
Statistical analysis All statistical analysis was performed using IBM SPSS Statistics 20 for Windows (Armonk, NY, USA). Continuous data were analyzed using paired t-test or Wilcoxon test, while Chi-square test and McNemar test were used for categorical and dichotomous variables, respectively. Statistical significance was assumed with P-value 2 vertebral bodies between the two esophageal pouches © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia Table 1 Baseline characteristics of patients (n = 20) Prevalence (%) Median (range) Gender Male 12 (60) Female 8 (40) Gestation (weeks) Age at diagnosis (months) Type of EA Proximal EA with distal TEF 16 (80) Isolated EA 2 (10) Isolated TEF 2 (10) Long-gap EA-TEF 5 (25) Associated anomalies VACTERL association 2 (10) CHARGE association 1 (5) Vertebral anomalies only 1 (5) Cardiac anomalies only 1 (5)
3
Eight patients were tested positive with egg, peanut and milk as the most common allergies. Treatment
37 (28–40) 26 (8–103)
EA-TEF, esophageal atresia/tracheoesophageal fistula; CHARGE, coloboma, heart defect, atresia choanae, retarded growth and development, genital and ear abnormalities; VACTERL, vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies and limb abnormalities.
is defined as long-gap EA), and two of the 5 LGEA patients were repaired by Foker procedure9 (refer to Table 1). Five patients had been fundoplicated in the past for GERD prior to their diagnosis of EoE. Only one of these was a LGEA. Both the LGEA who were repaired using Foker technique had not been fundoplicated as their reflux was well controlled on medical therapy. Of the 20 patients, 14 (70%) had a history of atopy. The most prevalent form of allergy was asthma, followed by food allergy and eczema (Table 2). Information on family history of atopy was collected in eight patients, positive in seven patients, commonest being history of asthma, rhinitis and eczema. Food allergy testing was conducted on 14 patients. Nine had both skin-prick tests (SPT) and radioallergosorbent test (RAST), four had only SPT, and one had only RAST. At our centre, a standardized panel for SPT was developed specially for EoE patients which consists of common allergens from major food groups (whole milk, egg white, peanut, soya, cashew, rye flour, rice, oats, corn, wheat, chicken, beef, cod, shrimp). For RAST, allergens that were frequently ordered consisted of dairy, nuts/ peanut, egg, wheat, soy, fish/shellfish and rice. Positive RAST results were always confirmed by SPT.
EoE was treated with either viscous budesonide slurry (n = 8), swallowed fluticasone (n = 5), elimination diet (targeted based on results of SPT or six food elimination diet or elemental amino acid based formula) (n = 1) or a combination of these therapies (n = 6).1,7,8 Budesonide slurry was dosed at 0.5–1.0 mg twice daily and swallowed fluticasone at 50–500 mcg taken as two puffs twice daily, depending on the age of the patients. Treatment with topical swallowed steroids was well tolerated with no adverse effects observed. Based on the results of RAST and SPT, targeted foods were also eliminated from diet if there were any positive results. The six-food elimination diet or elemental formula was used only in patients with poor response to targeted food elimination or with medication alone. Two patients were on elemental formula. One of them had severe eczema and was on six food elimination and targeted food elimination diet in addition to an elemental amino acid based formula. The other patient was treated with amino acid-based formula for 8 weeks following poor response of the EoE on a repeat endoscopy to budesonide slurry in combination with targeted food elimination diet. At the time of diagnosis of EoE, all patients were also on PPIs for GERD. This was continued throughout the treatment period in addition to EoE-specific therapy. PPI therapy was administered at a standard dose of at least 1 mg/kg/dose, once or twice daily. Endoscopic appearance Endoscopy reports at baseline, and final follow-up were reviewed. Seven out of 20 patients (35%) had a typical endoscopic evidence of EoE in the form of longitudinal furrowing and/or white exudates (Fig. 1). At follow-up endoscopy, six out of seven (86%) patients had normal endoscopic appearance, at a median follow-up period of 26 months, with resolution of the furrowing and exudates (P = 0.031). The one patient in whom the furrowing persisted was poorly compliant to EoE treatment. Strictures
Table 2 Results of allergy testing in study group Types of allergy
Number of patients (%)
Positive atopic history 1 type of atopic disease ≥2 atopic diseases Asthma Food allergy Eczema Rhinitis
14 (70) 6 (30) 8 (40) 11 (55) 8 (40) 6 (30) 1 (5)
© 2015 International Society for Diseases of the Esophagus
Eight out of 20 (40%) patients had strictures at baseline endoscopy at time of diagnosis of EoE (Fig. 2a and 2b). Six out of eight patients were treated with endoscopic balloon dilatations at time of diagnosis of EoE. In the other two, the luminal diameter of the esophagus at the level of previously documented stricture improved on progress endoscopy, in association with improvement in symptoms on medical treatment of EoE with topical swallowed budesonide
4
Diseases of the Esophagus
(a)
of EoE annually was 1.9 (Fig. 3b). Post-treatment of EoE, three of these 12 patients (P = 0.004) developed new strictures which required further dilatations to improve luminal diameter at site of strictures resulting in symptomatic improvement, with a mean of 0.9 dilatation per patient annually (P = 0.005). Histology Intraepithelial eosinophil count
Eosinophil counts per high-powered field were reduced at follow-up biopsies in 17 of 20 patients
(b)
Fig. 1 Pretreatment endoscopic evidence of EoE in EA-TEF patient. (a) Longitudinal furrowing. (b) White exudate.
slurry alone without need for dilatation. Figure 2b shows a stricture with narrowing of the esophageal lumen at time of initial diagnosis of EoE. After medical treatment of EoE, there was an improvement in the luminal diameter of the esophagus at the site of the previously documented stricture as shown in Figure 2c in the same patient. Due to this improvement in the luminal diameter on medical treatment of EoE, an appropriately sized endoscope was able to traverse the stricture in this patient. The locations of strictures were documented in seven patients, and in six of seven, the stricture was at the site of EA repair/ anastomosis. In follow-up endoscopy at a median of 28 months (range 23–132), only one patient was found to have stricture (P = 0.016) and which was endoscopically dilated. Patients who did not present with strictures at baseline did not develop strictures subsequently (Fig. 3a). Esophageal dilatation Twelve patients had strictures requiring at least one dilatation prior to EoE diagnosis and treatment. The mean number of dilatations per patient pre-diagnosis
Fig. 2 (a) Barium swallow of a symptomatic EoE stricture in EA-TEF patient. (b) Pretreatment EoE stricture in a EA-TEF patient. (c) Post-treatment endoscopic improvement of esophageal stricture with medical treatment alone in the same patient. © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
5
(a)
(b)
Fig. 3 (a) Number of patients with strictures at baseline and follow-up endoscopies (P = 0.016). (b) Number of dilatations per patient annually at baseline and at follow-up (P = 0.005).
(Fig. 5a and 5b). Peak intraepithelial eosinophil count was significantly reduced from a median of 30/HPF (range 19–80/HPF) at baseline to 8/HPF (range 0–85/HPF) at follow-up biopsies (P = 0.015) (Fig. 4). Median eosinophil count in the proximal esophageal biopsies reduced from 19 to 0 (P = 0.123), and those in the distal esophageal biopsies reduced from 30 to 10 (P = 0.013) Figure 5 shows an improve-
Fig. 5 (a) Pretreatment histological slide of EA-TEF patient with EoE showing an increase in intraepithelial eosinophils. (b) Post-treatment slide of the same EA-TEF patient showing histological improvement with reduction in the number of intraepithelial eosinophils.
ment in the esophageal histology with reduced eosinophil numbers post treatment of EoE. Median time between baseline and follow-up biopsies was 24 months (2–132 months). When the patients were categorized according to the type of treatment received for EoE, there was a reduction in peak eosinophil count irrespective of the type of EoE treatment (Fig. 6), although it was only in those patients who received a combination therapy of diet and swallowed steroids was there a significant reduction in the peak eosinophil count (P = 0.001). Other histological changes
Fig. 4 Peak intraepithelial eosinophil count at baseline and post-treatment biopsies (P = 0.015). © 2015 International Society for Diseases of the Esophagus
Reactive changes associated with EoE were compared at baseline and at follow-up biopsies. All patients had at least one of the three forms of reactive changes at baseline. Eight (40%) patients had subepithelial hyalinization, 17 (85%) had spongiosis, 19 (95%) had basal cell hyperplasia, and 19 (95%) had lamina propria elongation, and 9/17 (53%) were noted to have parakeratosis at baseline. After treatment, four of eight (50%) patients had complete resolution of hyalinization. There was also a significant
6
Diseases of the Esophagus
Fig. 6 Peak intraepithelial eosinophil count at baseline and follow-up biopsies with different treatment modalities.
Fig. 8 Number of symptomatic patients at baseline and at follow-up.
reduction in the severity of spongiosis, basal cell hyperplasia, lamina propria elongation and parakeratosis were reported in 11/17 (65%), 12/19 (63%), 13/19 (68%) and 6/9 (67%) patients, respectively (Fig. 7).
toms improved after therapy (P < 0.001). No child had food bolus impaction requiring endoscopic removal post-EoE treatment. Two patients experienced ‘dying/cyanotic spells’ pretreatment of EoE. Post-treatment of EoE, these patients no longer experienced these spells (Fig. 8).
Gastrostomy
Growth and nutrition
At time of diagnosis of EoE, there were six patients who had gastrostomy in situ. Post EoE treatment, four patients had closures of their gastrostomy within 12 months (P = 0.125). In two patients, a gastrostomy was inserted during the course of EoE treatment. One patient had it inserted due to the presence of a laryngeal cleft, to improve nutrition and help with administration of the elemental formula. Subsequent to the repair of the laryngeal cleft and improvement of EoE on elemental formula, an oral diet has been reintroduced. In the other patient, the gastrostomy was inserted to help improve nutrition. Symptoms
Dysphagia was seen in 80% and food bolus impaction was seen in 5% of our patients at baseline at time of diagnosis of EoE. Seventy-five percent also reported reflux symptoms. Both dysphagia and reflux symp-
Fig. 7 Number of patients with reactive changes at baseline and at follow-up.
The growth of patients was determined by their ageadjusted weight and height z-scores. Mean weight z-score improved from −1.28 to −0.89 (P = 0.156). Thirteen patients had paired height measurements recorded at baseline and follow-up. The mean height z-score improved from −0.92 to −0.80 (P = 0.558).
DISCUSSION Eosinophilic esophagitis is a condition that is becoming increasingly recognized as a distinct disease entity from other esophageal eosinophilia conditions such as reflux esophagitis.10 The prevalence of EoE in the children is reported to be at 0.89 to 4.30 per 10 000 children in different countries.11–13 Recently, there were reports demonstrating a greater prevalence of EoE in patients with EA-TEF as compared to the general pediatric population.3–5 Prevalence of EoE was reported to be at 17% and 1 in 80 in children with EA-TEF.3,14 There are several hypotheses to explain the increased prevalence of EoE in patients with EA-TEF. Esophageal dysmotility as a result of EA-TEF repair could prolong contact between food antigens and esophageal mucosa, predisposing to EoE.15 In addition, long-term follow-up studies have demonstrated that chronic GERD is prevalent in 35% to 58% patients long after EA-TEF repair.6,16 When chronically exposed to acid, the esophageal mucosa becomes permeable to small peptides up to 20 kd that would normally be impermeable in normal esophageal mucosa, which could potentially result in sensitization of food allergens in deeper layer of the © 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
esophagus.17 Due to chronic GERD, EA-TEF patients are often put on long-term PPI therapy. This early and prolonged exposure to PPI could prevent breaking down of food antigens thereby increasing the potential for sensitization to certain food antigens which may lead to the development of EoE.18 Genetic similarities between EA-TEF and EoE have also been reported.14 Despite the greater prevalence of EoE in EA-TEF patients as well as the genetic and pathophysiological associations between these two diseases, there is a possibility that EoE could have developed separately from EA-TEF and the responses of the EA-TEF patients to standard EoE treatment may not be of any different from non-EA-TEF patients with EoE. The first comprehensive diagnostic and management consensus recommendations for EoE was first published in 2007.19 Subsequently, several other papers had been published including the updated consensus recommendation and the American College of Gastroenterology Clinical Guidelines.1,7,8 These consensus recommendations agreed on using the three main management options for EoE – medications (budesonide slurry and swallowed fluticasone), dietary (elemental, empirical and targeted elimination diets) and esophageal dilatations. Our study is the first to investigate the treatment outcomes of EoE in EA-TEF children. The EoE treatment that our study group received was consistent with current recommendations. In our institution, topical steroids are prescribed as an initial therapy for EoE either in the form of budesonide slurry or swallowed fluticasone. Dietary elimination therapy is reserved for those patients who fail to improve clinically and histologically with topical steroids. EA-TEF children often concurrently have significant feeding difficulties, failure to thrive and GERD, and these families find the addition of a restrictive diet often too difficult to comply with. No patients required the use of systemic steroids in this study. Esophageal dilatations were reserved for symptomatic patients who have persisting strictures despite pharmacological and dietary therapy for their EoE. Our study is the first to demonstrate that the treatment of EoE in children with EA-TEF not only significantly reduces intraepithelial eosinophil count and reactive changes associated with EoE, but it also significantly reduces stricture occurrence and improves dysphagia and reflux symptoms. The intraepithelial eosinophil count was significantly reduced in 17 patients, particularly with the combination of topical steroids and elimination diet. The other three patients who had an increase in intraepithelial eosinophil count were noncompliant to treatment. The incidence of strictures significantly reduced post-treatment of EoE and the number of dilata© 2015 International Society for Diseases of the Esophagus
7
tions required per patient annually was also significantly reduced. None of our patients required endoscopic removal of food bolus impaction posttreatment, reflecting an improvement in the stricture incidence. As strictures are common in EA-TEF patients,20 our study highlights the importance of excluding EoE in EA-TEF patients with recurrent strictures and not proceeding fundoplication routinely in these patients, as not only GERD but also EoE can result in recurrent strictures. The improvement in strictures in two patients on treatment of EoE alone without need for endoscopic dilatation also underlines the absolute need for endoscopy with biopsies prior to dilatation of strictures in EA-TEF patients with recurrent strictures and increasing dysphagia. We feel that the ability of an age appropriate endoscope to traverse the esophagus due to an improvement in the luminal diameter at the site of a previously documented stricture after medical therapy of EoE could be used as an objective parameter to support the effectiveness of the medical therapy of EoE in patients with strictures secondary to EoE in addition to an improvement in the histology. Post EoE treatment, gastrostomy closures were performed on four of six patients, suggesting EoE may have been contributing to the feeding difficulties. However, given the small number of patients, it is difficult to determine the efficacy of EoE treatment on feeding improvement and weaning from gastrostomy feeds. A larger prospective study would be required to establish this association. We feel that our results highlight the importance of excluding not only GERD but also EoE in EA-TEF patients with feeding difficulties and failure to thrive in order to avoid further unnecessary surgical interventions. In our study, there was trend towards a nonsignificant improvement in weight and height z-scores in patients’ post-treatment of their EoE. The lack of significance could have been due to the small numbers, the fact that the follow-up was not of the same duration in all patients and that in EA-TEF patients there could be other causes for poor weight gain.6 This also highlights the need for long-term follow-up studies on treatment in EA-TEF patients with EoE. There was a significant symptomatic improvement in dysphagia and reflux symptoms, both of which were the most common complaints in the EA-TEF cohort.21 This symptomatic improvement could be due to the reduced inflammation leading to improved esophageal motility and clearance of refluxate. Interestingly, the two patients who reported ‘hypoxic/ cyanotic spells’ pretreatment of EoE had no further episodes post-treatment. The etiology of these spells in the EA-TEF is thought to be multifactorial with esophageal dysmotility, GERD, strictures and tracheomalacia all thought to play a role.22 We
8
Diseases of the Esophagus
hypothesize that EoE treatment, by improving esophageal motility, clearance of refluxate and reducing stricture incidence, could potentially lead to a reduction in the incidence of these ‘hypoxic/cyanotic spells’. We therefore feel that it is important to exclude EoE in EA-TEF patients with “hypoxic/ cyanotic spells” before proceeding to aortopexy or fundoplication which are the standard treatment options for this condition. We acknowledge that our study had only small number of patients, and larger prospective trials will be needed to confirm our findings. In addition, as the natural history of EA-TEF is not well defined, prior esophageal dilatations may have impacted on subsequent clinical symptoms and need for repeated dilatations. Therefore, there is possibility that the improved outcomes may not have been directly related solely to EoE therapy alone. Of the four patients who had fundoplication at baseline, the mean time from fundoplication to the diagnosis of EoE was 23 months (range 20–25 months). It is difficult to determine whether patients who underwent fundoplication prior to the diagnosis of EoE were symptomatic at the time of their surgery as a result of severe reflux symptoms or undiagnosed EoE or both. The similarity of symptoms observed in GERD and EoE makes it difficult to differentiate between both in the absence of endoscopy and biopsy and pH monitoring. However, given the significant improvement in reflux symptoms post-EoE treatment, we feel that it is important to exclude EoE with an endoscopy and biopsy prior to considering fundoplication in EA-TEF patients with persistent symptoms on medical treatment for their GERD symptoms. There have been reports in literature of PPIresponsive eosinophilia but we feel that our cohort represents true EoE rather than this condition as all our patients were on standard doses of PPI at baseline at the time of diagnosis of their EoE. However, we agree with the consensus guidelines on EoE published earlier1,7,8 that if ≥15 eosinophils/HPF are seen on biopsy in patient not on PPI, then as a first step, these patients should be initially trialed on PPI in standard doses and then have a repeat endoscopy and biopsy. If there is persistent eosinophilia of ≥15 eos/HPF, only then should they proceed to standard EoE treatment. This is especially important in the EA-TEF cohort who has a high incidence of GERD.6,16 Improvement in histology, endoscopy and symptoms has been reported in several studies that investigated the use of oral steroids and elimination diet in children with EoE.23,24 However, relapses were observed once treatments were stopped. A retrospective study by Liacouras et al. reported that 50% of patients have recurrence of symptoms and worsening histology at 12 months post cessation of treatment despite initial improvement or resolution of symp-
toms post-treatment.25 Similarly in Schaefer et al.’s study, the participants received a 4-week treatment followed by 8 weeks weaning protocol had histological and symptomatic improvement at 4 weeks, but 45% of the participants relapsed at 24 weeks.26 In our study, two patients discontinued treatment after 77 and 8 months of treatment with elimination diet and swallowed fluticasone, respectively, and 15 months later there is no sign of relapse clinically or histopathologically. However in two other patients who were noncompliant to treatment did experience clinical and histopathological recurrence and treatment reinitiated. This shows the importance of maintenance therapy in EoE even after inducing remission in order to avoid relapses. Long-term follow-up studies would be needed to determine the optimal duration of treatment to maintain remission of EoE. In conclusion, our study has shown that treating EoE in children with EA-TEF leads to not only mucosal healing but also results in a significant improvement in clinical symptoms, stricture recurrence and the subsequent need for dilatations. We feel that the results of this study underline the importance and absolute need for endoscopic biopsy at the time of stricture dilatation in EA-TEF patients. We also recommend endoscopy with biopsies in EA-TEF patients with increasing dysphagia, recurrent strictures, feeding difficulties being considered for gastrostomy placement and particularly in those with persistent symptoms on PPI prior to consideration for surgical procedures such as fundoplication for recurrent strictures. We feel that it is important in the future to do long-term follow-up studies in the cohort of EA-TEF patients with EoE to determine treatment outcomes including effect on growth and nutrition over a longer time period. Our team is currently involved in a prospective study aiming to determine whether there is an improvement in the quality of life of these patients post-treatment of their EoE. References 1 Liacouras C A, Furuta G T, Hirano I et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011; 128: 3–20. 2 Dellon E S. Diagnosis and management of eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012; 10: 1066–78. 3 Dhaliwal J, Tobias V, Sugo E et al. Eosinophilic esophagitis in children with esophageal atresia. Dis Esophagus 2014; 27: 340–7. 4 Batres L A, Liacouras C, Schnaufer L, Mascarenhas M R. Eosinophilic esophagitis associated with anastomotic strictures after esophageal atresia repair. J Pediatr Gastroenterol Nutr 2002; 35: 224–6. 5 Oliveira C, Zamakhshary M, Marcon P, Kim P C. Eosinophilic esophagitis and intermediate esophagitis after tracheoesophageal fistula repair: a case series. J Pediatr Surg 2008; 43: 810–4. 6 Kovesi T, Rubin S. Long-term complications of congenital esophageal atresia and/or tracheoesophageal fistula. Chest 2004; 126: 915–25. 7 Dellon E S, Gonsalves N, Hirano I et al. ACG clinical guideline: evidenced based approach to the diagnosis and manage© 2015 International Society for Diseases of the Esophagus
Eosinophilic esophagitis in esophageal atresia
8 9 10 11 12 13 14
15
16
17
ment of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013; 108: 679–92. Papadopoulou A, Koletzko S, Heuschkel R et al. Management guidelines of eosinophilic esophagitis in childhood. J Pediatr Gastroenterol Nutr 2014; 58: 107–18. Nasr A, Langer J C. Mechanical traction techniques for longgap esophageal atresia: a critical appraisal. Eur J Pediatr Surg 2013; 23: 191–7. Liacouras C A. Eosinophilic esophagitis in children and adults. J Pediatr Gastroenterol Nutr 2003; 37 (Suppl. 1): S23–8. Noel R J, Putnam P E, Rothenberg M E. Eosinophilic Esophagitis. NEJM 2004; 351: 940–1. Cherian S, Smith N M, Forbes D A. Rapidly increasing prevalence of eosinophilic oesophagitis in Western Australia. Arch Dis Child 2006; 91: 1000–4. Furuta G T, Straumann A. Review article: the pathogenesis and management of eosinophilic oesophagitis. Aliment Pharmacol Ther 2006; 24: 173–82. Gorter R R, Heij H A, van der Voorn J P, Kneepkens C M F. Eosinophilic esophagitis after esophageal atresia: is there an association? Case presentation and literature review. J Pediatr Surg 2012; 47: e9–13. Deurloo J A, Klinkenberg E C, Ekkelkamp S et al. Adults with corrected oesophageal atresia: is oesophageal function associated with complaints and/or quality of life? Pediatr Surg Int 2008; 24: 537–41. Deurloo J A, Ekkelkamp S, Bartelsman J F et al. Gastroesophageal reflux: prevalence in adults older than 28 years after correction of esophageal atresia. Ann Surg 2003; 238: 686–9. Tobey N A, Carson J L, Alkiek R A, Orlando R C. Dilated intercellular spaces: a morphological feature of acid reflux – damaged human esophageal epithelium. Gastroenterology 1996; 111: 1200–5.
© 2015 International Society for Diseases of the Esophagus
9
18 Pali-Schöll I, Jensen-Jarolim E. Anti-acid medication as a risk factor for food allergy. Allergy 2011; 66: 469–77. 19 Furuta G T, Liacouras C A, Collins M H et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007; 133: 1342–63. 20 Serhal L, Gottrand F, Sfeir R et al. Anastomotic stricture after surgical repair of esophageal atresia: frequency, risk factors, and efficacy of esophageal bougie dilatations. J Pediatr Surg 2010; 45: 1459–62. 21 Little D C, Rescorla F J, Grosfeld J L et al. Long-term analysis of children with esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003; 38: 852–6. 22 Shah R, Varjavandi V, Krishnan U. Predictive factors for complications in children with esophageal atresia and tracheoesophageal fistula. Dis Esophagus 2014; 28: 216–223. doi: 10.1111/dote.12177 23 Aceves S S, Bastian J F, Newbury R O, Dohil R. Oral viscous budesonide: a potential new therapy for eosinophilic esophagitis in children. Am J Gastroenterol 2007; 102: 2271–9, quiz 2280. 24 Markowitz J E, Spergel J M, Ruchelli E, Liacouras C A. Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol 2003; 98: 777–82. 25 Liacouras C A, Wenner W J, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998; 26: 380–5. 26 Schaefer E T, Fitzgerald J F, Molleston J P et al. Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clin Gastroenterol Hepatol 2008; 6: 165–73.
