All 27 children with ECD had symptoms of lower gastrointestinal tract involvement. However, clinical symptoms suggestive of upper gastrointestinal tract involvement were found in only 9 children. The symptoms included dysphagia (6 cases), heartburn (5 cases), vomiting (5 cases), and odynophagia (1 case). A combination of these symptoms was seen in 5 cases. The remaining 18 children who were found to have incidental ECD detected at endoscopic evaluation for their ileo-colonic symptoms were grouped as asymptomatic ECD. Extra intestinal manifestations identified in 25.9% of cases included erythema nodosum (2), aphthous mouth ulcers (3), episcleritis (1), and arthritis (1). Extra intestinal manifestations were found in 22.4% in children with Crohn disease without esophageal involvement. A family history of IBD was present in 44.4% of ECD patients compared to 30.9% of patients with Crohn disease and no esophageal involvement.
Endoscopy and Radiologic Studies
All 27 children with ECD had a barium small bowel follow-through study within 6 to 8 weeks of the endoscopic examination. None of the children had detectable radiologic signs of CD in the upper gastrointestinal tract. Combining radiology and colonoscopy findings identified ileo-colonic involvement in 18 children, isolated small bowel disease in 3 children, and isolated colonic disease in 6 children (Fig. 2).
In symptomatic ECD patients, endoscopy identified deep ulcers in 2 patients, erosions, aphthous ulcers, and erythematous nodules each in 1 patient, and normal-looking mucosa in 4 patients. Histological evidence of ECD was evident in all symptomatic patients. In the asymptomatic patients, 5 children had aphthous ulcers, 3 children had deep ulcers, and 3 children had erosions. The remaining 7 children had normal-looking mucosa but showed histology evidence of Crohn disease.
Gastroduodenal involvement was detected endoscopically in all symptomatic children and in 17 of 18 asymptomatic children (Fig. 2), including 20 cases of gastric CD, 3 cases of duodenal CD, and 3 cases of both gastric and duodenal CD. Endoscopic and/or histologic evidence of CD of the stomach and/or duodenum were also found in 95 of 117 (81%) children without ECD (Fig. 1).
Esophageal inflammation was evident in 25 of 27 patients. Esophageal biopsies included epithelium with lymphocytosis in 17 children and acute inflammation in 13 cases. Epithelial ulceration was noticed in 5 cases along with granulation tissue and chronic inflammatory cell infiltrates. Presence of lamina propria was documented in 16 specimens. All of those specimens showed focal chronic inflammation with plasma cells, lymphocytes that extended into the lamina propria. Noncaseating granulomata were identified in 7 of 27 (25%) of the children. In the 2 children with unremarkable histology, aphthous ulcers were noted at endoscopy.
Treatment and Outcome
The mean duration of follow-up for the 9 children with upper gastrointestinal symptoms and ECD was 3.1 years (7 months to 5 years). Our group uses acid suppression in the treatment of ECD only in children with specific upper gastrointestinal symptoms and/or endoscopic lesions. Seven of these children were treated with acid suppressant medications (omeprazole n = 5, ranitidine n = 2) along with treatment for ileo-colonic disease. Omeprazole was started at 1.4 mg/kg/d in a single morning dose and ranitidine was given 4 to 6 mg/kg/d in two divided doses. The two children who presented with nausea and vomiting and only microscopic ECD were not given any specific acid suppressive treatment.
However, one child had an ileo-colonic resection for persistent lower gastrointestinal symptoms and the other child received a 5-ASA compound and steroids. Neither child had any recurrence of symptoms. During the last visit, 3 children were receiving acid suppression and one child was still symptomatic. In the remaining 4 children, acid suppression was discontinued with resolution of gastrointestinal symptoms.
Of the 9 symptomatic ECD children, 4 children required 6-MP because of steroid dependency. Two of these children required an ileo-colonic resection with primary anastomosis and one had a stricturoplasty, small bowel resection, and right hemicolectomy.
The mean duration of follow-up of the asymptomatic ECD group was 3.0 years (2 months—11.7 years). Two children presenting with deep ulcers were treated with omeprazole. The remaining children received treatment only for ileo-colonic disease. In this group, 2 children required a right hemicolectomy and one child had a subtotal colectomy for refractory Crohn colitis following an unsuccessful trial with intravenous cyclosporine. Three children were steroid dependent and required 6-MP in their management. Four children reported heartburn and nausea once their diarrhea and anorexia were controlled by steroids and/or nutritional supplementation. Three of them received omeprazole and one had ranitidine.
None of the children with ECD developed esophageal complications such as stricture or stenosis or fistulae during the follow-up period.
Of the 144 children with IBD who underwent an UGI endoscopy, 16 children had endoscopic evidence of ECD and 11 children had only histologic findings. The lowest estimate of the prevalence of ECD based on endoscopic validated cases alone is therefore 16 of 210 (7.6%). Including histologic findings as evidence for ECD, the prevalence is 27 of 210 (12.8%). The actual prevalence may have been higher if all children with CD had had an upper GI endoscopy. This prevalence can be estimated first by calculating the prevalence of asymptomatic ECD in those who had undergone upper GI endoscopy (18/118 = 15.2%; see Figure 1). Then apply this ratio to the number of children with no upper gastrointestinal symptoms who did not have an upper GI endoscopy (210–144 = 66 children; see Figure 1). Calculations predict that an additional 10 children with ECD would have been detected bringing the total children with ECD to 37 of 210. Thus the estimated prevalence of ECD in our patient population is 17.6%.
This large cohort of 210 children with Crohn disease allows for the determination of a reliable estimate of the prevalence of esophageal Crohn disease and correlation of clinical course to endoscopic findings.
Reports on the prevalence of ECD vary widely in both adults and pediatrics. Decker et al. (2) previously reported that only 20 of 9900 (0.2%) adults with CD seen over a period of 22 years had ECD. A higher prevalence was reported by D'Haens (3) who demonstrated ECD in 14 of 124 (11%) adults with CD investigated with upper GI endoscopy over a period of 12 years. Both of these studies were retrospective and used macroscopic endoscopic evidence as the only criteria for diagnosis that likely resulted in an underestimation of the prevalence. In the only prospective study of ECD in adults a prevalence of 5.1% was seen (9). In the pediatric age group there have been few prospective and retrospective studies that provide estimates of the prevalence of ECD. In one prospective study, endoscopy identified in ECD 2 of 40 (5%) children with CD and a total of 17 of 40 (42.5%) had histologic evidence of ECD (7). Additional prospective studies detected ECD in 8 of 31 (26%) children based on either endoscopic or histologic findings (6) and in 7 of 56 (13%) based on macroscopic findings alone (5). In our study the lowest estimate of prevalence for endoscopic ECD was 7.6% and the highest estimate was 17.6% when including histology findings as diagnostic criteria. These findings suggest that the prevalence of ECD in adults and children may be similar and is at least 5%. Low estimates in some of the retrospective adult studies may be a reflection of patient selection for UGI endoscopy.
There is wide variability in the clinical manifestations of ECD and many patients do not have specific symptoms related to ECD. Moreover, isolated esophageal Crohn disease is uncommon (10) and in our study no children were identified with isolated ECD.
Esophageal Crohn disease is usually associated with advanced ileo-colonic disease (1,11). In our study group, 10 children had severe extraesophageal CD, and 7 of them were on 6-MP and 6 of these children required surgery which indirectly reflects the severity of extra esophageal CD. All children in the study had evidence of ileo-colonic involvement. Previous reports have suggested that there is an increased association of extraintestinal manifestations with ECD (1,11). However in our study 25.9% of patients had extra intestinal manifestations which was similar to the rate of extra-intestinal manifestations seen in children with CD and no esophageal involvement (22.4%).
In two different prospective studies by Cameron (5) and Mashako (6), upper GI symptoms were present in only 15% and 25% of children with CD. However the prevalence of upper GI tract abnormalities ranged from 42% to 71% respectively. Alcantara found that 17% of 41 adults had upper gastrointestinal symptoms but only 5% had endoscopic ECD (9). In our study 33% of the children with ECD had specific upper GI symptoms. According to Lenaerts (4), dysphagia and/or epigastric pain, nausea and vomiting were noticed more frequently in children with upper gastrointestinal CD but were also seen in children without upper GI disease, suggesting that these symptoms are not specific to the upper GI tract disease. In our study there was no difference in the endoscopic findings for those ECD children with symptoms and those children without symptoms. In the pediatric age group, there is often an overlap of symptoms (such as nausea, anorexia, and abdominal pain) between esophageal and small bowel CD. It is therefore difficult to identify an upper gastrointestinal site of disease based on clinical evaluation alone. Thus UGI endoscopy and biopsies are important in the evaluation of pediatric IBD, even in the asymptomatic child.
The presence of histologic abnormalities in radiologically and endoscopically normal mucosa has been well described (12). Hence, endoscopy with biopsy is generally considered the gold standard for diagnosis of early lesions that may be asymptomatic. Huchzermeyer et al. (13) have previously observed that the spectrum of esophageal injury in Crohn disease varied from mild esophagitis with small erosions to transmural involvement with esophageal perforation and fistulization to adjacent organs. In addition to aphthous ulcers, other findings well described in ECD are the presence of erythema, ulceration, erythematous nodules, and polypoid lesions (14). Pseudomembrane formations, progressive esophageal narrowing resulting in strictures and formations of multiple mucosal bridges have been described in advanced stages of ECD (15).
Epithelioid granulomatas are considered diagnostic for Crohn disease. Seven of 27 (25%) of our patients had granulomas in the esophageal biopsy specimen. In a review of the literature, granulomas were documented in 39% of patients with ECD detected at endoscopy with biopsy and on some surgically resected specimens (16). Focal infiltration with mononuclear cells and histiocytes into the lamina propria that extends to the muscular layer is often considered histologic evidence of Crohn esophagitis (3,8). These changes in lamina propria often help to differentiate ECD from other causes of epithelitis. Presence of intraepithelial lymphocytes with irregular nuclear contour is also a diagnostic feature, but not pathognomonic (17).
Management of esophageal Crohn disease is highly variable. Case studies have shown that steroids were effective in controlling inflammation (18,19). However, upper gastrointestinal symptoms may be effectively managed with acid suppression rather than steroids. Interestingly, four of our children in the asymptomatic category become aware of heartburn and epigastric pain only after their lower gastrointestinal symptoms were controlled with standard induction treatment. These symptoms were well controlled with acid suppressive medications.
Our group has adopted the approach of using acid suppression treatment for ECD only in children with specific upper gastrointestinal symptoms and/or endoscopic lesions. However, microscopic inflammatory changes per se were not considered as indication for treatment. The small number of children who were treated with acid suppression and the variation in disease involvement preclude a direct comparison of omeprazole and ranitidine for the symptomatic ECD.
Duration of acid suppressive medication is dependent upon the periodic reappraisal of symptoms during follow-up. Meihsler et al. (20), using gastroduodenal and intestinal permeability studies in patients with upper GI Crohn lesions, have shown that symptom scores consistently decreased following treatment with antisecretory drugs, despite no change in intestinal permeability.
In a study by Decker et al. (2), 11 of 20 adult patients with ECD received either azothioprine, 6-mercaptopurine, cyclosporin A alone or in combination with steroids for the management of refractory esophageal Crohn disease and coexisting extra esophageal lesions. However, in this study only 6 patients among 11 responded to immunomodulator therapy. Three of those who received immunomodulators (27.2%) showed improvement on azothioprine or 6-MP together with steroids and one patient responded to cyclosoprine A with esophageal dilations. Two of the responders received immunomodulatory therapy primarily for extraesophageal CD. Hence it is difficult to judge the true efficacy of immunomodulators in resistant ECD. Moreover, randomized controlled trials using various therapeutic agents in the management of ECD patients have been faced with the problem of recruiting adequate numbers.
The natural course of esophageal Crohn disease has previously been described by D'haens et al (3), who showed that 57% (8/14) of their patients had no recurrence of esophageal lesions or symptoms during subsequent flare-up. Three patients with flare up (21.4%) had persistent lesions despite corticosteroid treatment. The remaining three (21.4%) with a flare up had a recurrence of esophageal symptoms and associated endoscopic lesions following complete healing with the initial treatment. None of the children in our study had repeat endoscopy for recurrence of upper gastrointestinal symptoms. Thus, the natural course of ECD in children remains poorly described and the outcome of those who presented with endoscopic lesions without symptoms remain unknown.
The clinical significance of histologic ECD can only be determined by a long-term follow-up and long-term endoscopic surveillance. Nevertheless, considering the high prevalence of histologic ECD in children throughout several different centers in the world and the low rates of endoscopic ECD in adults it may be reasonable to postulate that histologic ECD is unlikely to progress to a more overt disease over time.
In conclusion, in our study all of our pediatric ECD patients were presented with ileo-colonic symptoms, but the majority of them were asymptomatic from their esophageal lesions. Currently there are no standardized treatment guidelines for patients with either specific upper gastrointestinal symptoms or without symptoms. Steroids are an effective therapy, however, recurrence of symptoms is commonly encountered during steroid withdrawal. Acid suppressive treatment has a definite role in controlling symptoms. Further controlled studies are required to follow the natural course of asymptomatic ECD in children and outcome of those managed with or without acid suppression.
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Keywords:© 2003 Lippincott Williams & Wilkins, Inc.
Crohn disease; Esophagus; Upper GI endoscopy; Prevalence