Background: Patients with eosinophilic esophagitis (EoE) present with mechanical type dysphagia. Barium esophagrams occasionally demonstrate focal strictures or multiple concentric rings. Diffuse narrowing has also been reported but may be difficult to recognize because of lack of normative data. Aim: The aim of this study is to assess esophageal diameters at multiple sites in healthy controls in comparison with EoE patients. Methods: A standardized barium swallow was performed in 22 healthy male volunteers without esophageal symptoms and compared with 10 untreated EoE patients. A radiopaque ruler aa tt ched at the subject’s back was used to measure maximal esophageal diameter at three esophageal sites by a blinded observer. Peak intraepithelial eosinophil counts and Mayo Dysphagia Questionnaire scores were correlated to esophageal diameters in EoE patients. Results: Two of 10 EoE patients had areas of focal narrowing on barium Xray. Esophageal diameters were significantly less at all three esophageal sites in EoE patients compared with controls. Using a total esophageal diameter score (i.e., sum of the three diameters) to establish the 95th percentile for mini- mal diameter in controls, four of 10 EoE patients fell below the normal range. There was no significant correlation between esophageal diameters, peak eosinophil counts and any of the Mayo Dysphagia Questionnaire severity scores. Conclusion: Patients with EoE have a diffusely narrow esophagus in comparison to healthy controls, and this abnormality may not be appreciated without using appropriate normative data. Keywords: Barium, Dysphagia, Eosinophils, Esophagus, Stricture, X-ray. Once considered a rare disorder, eosinophilic esophagitis be reported as normal in EoE patients, but in some patients, (EoE) is now recognized as a common cause of solid food dys- focal strictures (especially proximal strictures) and multiple phagia and food bolus obstruction, particularly in young adult concentric rings may also be seen (4). The lae tt r is felt to be males (1). EoE is diagnosed by the finding of ≥15 eosinophils characteristic of the disorder (5). In addition, a diffusely nar - per high-powered field on esophageal mucosal biopsies in row-calibre esophagus has been described on barium esopha- patients with esophageal symptoms in whom gastroesophageal grams in a small subset of EoE patients (6). Focal abnormalities reflux disease has been excluded (2). Although endoscopy may are more readily appreciated by radiologists, and although dif- be normal, a number of macroscopic abnormalities have been fuse narrowing may be recognized when marked, more subtle described, including linear furrowing, trachealization, focal and degrees of diffuse calibre change are likely overlooked, particu- diffuse structuring, mucosal trauma and scae tt red small white larly given that we have no well-established normative data on exudates (3). Similarly, barium contrast esophagrams may also esophageal diameter as measured by barium esophagrams. © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy022/5003195 provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org by Ed 'DeepDyve' Gillespie user on 07 June 2018 2 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Recent studies have provided some useful, albeit limited, Hematoxylin phloxine and saffron-stained 5-µm-thick sections objective data in this area (6, 7). Lee et al. (7) reported nor- of endoscopically obtained esophageal mucosal biopsies were mal values for esophageal diameter in 10 control subjects and reviewed. Eosinophilic inflammation was assessed by count - demonstrated that these measures were reproducible. Their ing intraepithelial eosinophils in five separate high-power standardized protocol involved having subjects rapidly drink fields for each case and then calculating the average number a 10-ounce cup of barium, following which they measured the of intraepithelial eosinophils for each case. As the eosinophilic maximal and minimal diameters of the thoracic esophagus at inflammation may be variable in intensity and also patchy in dis - maximal distension. Roughly half of 11 EoE patients studied in tribution, counts were obtained from areas where the intraepi- an identical fashion were found to have esophageal diameters thelial inflammation was most intense. Area of actual epithelium that fell outside the normal range, and when these patients were within a given microscopic field was not directly controlled (i.e., subsequently treated with topical steroids, esophageal diame- the actual area of epithelium varied from field to field); how - ter was seen to normalize. It is noteworthy, however, that the ever, in all cases, the microscopic field was filled at least 75% by vast majority of patients and controls studied were female, even epithelium. This way, the epithelial area between cases that was though EoE is predominantly a disease of young men. assessed is considered to be relatively equal, allowing compari- In the current study, we established normal diameters at three dif- son of the eosinophil counts observed. ferent esophageal sites using barium contrast radiography in 22 male Statistical Analysis control subjects and compared these with 10 male EoE patients. Comparisons of baseline demographics and esophageal diameters between controls and EoE subjects was performed using unpaired METHODS t-tests. The Spearman rank correlation was used to determine The study was approved by the research ethics board at Queen’s whether there was a correlation between esophageal diameter, University, and all participants provided informed, written con- mucosal eosinophil counts, parameters of the Mayo dysphagia sent. A total of 22 healthy male volunteers were recruited. To be questionnaire and subject height and esophageal diameter. eligible, they had to be free of esophageal symptoms and have no major co-morbid illnesses. Ten male eosinophilic esoph- RESULTS agitis patients were recruited. To be eligible, they had to have Table 1 summarizes the baseline characteristics of the control >15 eosinophils per high-powered field on esophageal mucosal and EoE subjects. As can be seen, age, weight and BMI were biopsy and be unresponsive to at least a two-month course of comparable between the two groups. There was a statistically proton pump inhibitor therapy. Patients with prior topical ste- significant difference in height, with the control group being roid treatment or esophageal dilation were excluded. We also taller. To determine whether this might have affected our results, excluded patients who had had a recent barium study for clini- we compared the average total esophageal diameter score (i.e., cal indications to avoid repeat X-ray exposure. the sum of the diameters in the three esophageal segments) to subject height. No significant correlation was found (r=0.1754; Barium Esophagram Protocol P=0.43, Spearman rank correlation). All participants underwent a standardized barium swallow. Focal radiological abnormalities were noted in only two of the They were positioned upright with a radiopaque ruler aa tt ched 10 EoE cases, both of whom had focal narrowing in the more at their back. They were then asked to swallow 150 mL of bar - proximal esophagus (Figure 1). As can be seen in Figure 2A, ium as quickly as possible. Spot films were then obtained when EoE patients had a significantly narrowed esophagus at all three the esophagus appeared maximally distended. The radiologist levels when compared with controls. In addition, the overall performing the barium swallow was blinded as to whether the diameter score was significantly less in EoE patients ( Figure 2B). subject was an EoE patient or control, and the spot films were coded and subsequently analyzed by a radiologist who was Table 1. Baseline characteristics of control subjects and EoE blinded as to whether the subject was a control or EoE patient. patients. Maximal diameter at three sites (just above the aortic arch, just above the gastroesophageal junction and half way in between) Control: mean EoE: mean P-value was measured. Eosinophilic esophagitis patients were asked to (range); n=22 (range); n=10 complete the Mayo dysphagia questionnaire (8). Age (yrs) 34.3 (18–62) 29.3 (18–51) 0.36 Weight (Kg) 81.9 (54–108) 82 (65–106) 0.88 Histology Height (M) 1.80 (1.7–1.9) 1.74 (1.6–1.9) 0.04 To establish a diagnosis of EoE, biopsies were routinely obtained BMI 25.3 (19.7–34.6) 27.4 (21.9–40.2) 0.3 from both the distal (~2–5 cm above the gastroesophageal junc- Allergic History 18.2% 45.4% 0.12 tion) and proximal (20–25 cm from the incisors) esophagus. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy022/5003195 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 3 To determine what proportion of patients fell outside the nor- It is worth noting that with gross inspection of the barium mal range, the 95th percentile for the esophageal diameter score esophagram, it is relatively easy to miss abnormal studies. was calculated in the control group. In four of the EoE cases, Figure 3 is an example of a spot film in an EoE patient and a this average diameter fell outside the normal range, including healthy control. The sum of three diameters in healthy control one of the two patients with focal strictures. in this instance was 6.13 cm, whereas in the EOE patient, it was 3.64 cm. Table 2 summarizes correlations between esophageal diam- eter, eosinophil counts and Mayo dysphagia questionnaire symptom scores in the patients with EoE. There is no statisti - cal correlation between diameter and any of these parameters. Overall, symptoms scores were not particularly high, with an average composite score (severity x frequency) of 9.4 (range 3.33–26), with a maximum possible score of 56. DISCUSSION The present study demonstrates EoE subjects tend to have a diffusely narrowed esophagus when compared with appropri - ately matched control subjects and suggests that this abnormal- ity may be underreported both clinically and in the literature. Esophageal diameters were significantly less in each of the prox - imal mid and distal esophageal segments in EoE patients versus controls, and four of 10 subjects fell outside the normal range Figure 1. Barium esophograms in the two EoE patients with focal stricturing in the mid to for average esophageal diameter as established by the 95th per- proximal esophagus. centile values in controls. Focal (especially proximal) esophageal strictures and multi- ple concentric rings are seen infrequently on barium studies in EoE patients but are readily apparent when present (Figure 1). A so-called narrow caliber esophagus has also been described in EoE patients, but because there is very limited data as to what constitutes a normal esophageal diameter on barium contrast studies, it is likely that this abnormality is reported only when the Figure 2. A) The esophageal diameter was significantly less in EoE patients compared with control subjects at all three esophageal locations (p=0.046, 0.006 and 0.02 at the proximal, Figure 3. Example of barium esophagrams in a healthy control subject (right) and a patient mid and distal locations, respectively). B) The total diameter score (sum of three diameters) with EoE (left). Although the images look comparable, the sum of the diameters from the was significantly less in EoE patients (p=0.002). Data presented as means +/- SEM. three esophageal locations was 6.13 cm in the control subject and 3.64 cm in the EoE patient. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy022/5003195 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Table 2. Correlations (Pearson) between esophageal diameter, eosinophil counts and Mayo dysphagia questionnaire symptom scores in EoE patients. Variable Average esophageal diameter P-value Smallest esophageal diameter P-value Maximum eosinophil count −0.438 0.238 −0.589 0.095 Dysphagia severity 0.120 0.776 0.284 0.496 Dysphagia frequency 0.119 0.779 0.291 0.485 Frequency x Severity 0.148 0.726 0.258 0.537 Dysphagia duration 0.337 0.415 −0.139 0.742 # foods avoided 0.378 0.356 0.527 0.179 Meal duration 0.018 0.966 −0.228 0.587 diffuse narrowing is severe and that milder degrees of narrowing dysphagia suggests that motor abnormalities likely play a sec- are overlooked. This is supported by the current study in which ondary role in the etiology of the dysphagia. Poor compliance 40% of our EoE patients had an abnormally narrow esophagus. has been demonstrated in EoE patients (10) in keeping with the Other groups have reported normal values for barium esopha- known fibrotic remodeling that can occur in the disease. This gram using standardized techniques, but the available data to lack of distensibility likely results in an inability to accommo- date is quite limited. W hite et. al. (6) used their radiological data- date to the passage of larger food boluses and probably plays a base to select 10 normal barium X-ray studies to develop nor- fundamental role in the etiology of dysphagia in EoE, reflux and mal values that they then compared with a small group of EoE other forms of esophagitis. Diffuse esophageal narrowing, even patients. Unfortunately, this normal group was not characterized if subtle, may well be the radiological equivalent of poor compli- in terms of possible esophageal symptoms and may not repre- ance. We suspect that in the six patients with esophageal diam- sent a true control group in a healthy asymptomatic population. eters that fell within the normal range, impaired compliance Subsequently, Lee et al. (7) performed standard barium X-rays likely played a key role in the pathogenesis of their dysphagia. in 10 subjects in order to establish normal values for maximum In the current study, we found no significant correlations and minimum diameters as measured when the esophagus was between the average esophageal diameter in EoE patients and maximally distended ae ft r the subject rapidly ingested 10 ounces eosinophil cell count or any of the metrics on the Mayo dys- of barium. Using the 10th and 90th percentile in their control phagia questionnaire. This is perhaps not surprising given the group, they established the normal range for minimal esopha- relatively small number of patients studied and the nature of geal diameter as 15.6–23.7 mm, and the normal range of maxi- the Mayo Dysphagia Questionnaire. Although comprehensive mal esophageal diameter as 21–27 mm. These investigators also and useful for measuring the impact of dysphagia on a patient, repeated the measurement and established the technique was this questionnaire is subjective and likely lacks precision with reproducible. Approximately half of the 11 EOE patients that respect to assessing objective severity of disease. Furthermore, they studied in an identical fashion were found to have esoph- the perception of dysphagia is undoubtedly influenced by sen- ageal diameters that fell below this normal range. Interestingly, sory and supratentorial factors. when following treatment with topical steroids, esophageal In summary, although endoscopy with esophageal biop- diameter tended to normalize in the subgroup of patients that sies is required to confirm a diagnosis of EoE, timely access had initially narrowed esophagus. Of note, this study was atypical to endoscopy is a problem in some regions, resulting in many in that only two of their 10 control subjects and three of their 11 patients still being referred for barium contrast studies. The EoE patients were males, which is not representative of the EoE current study demonstrates that diffuse esophageal narrowing population that generally is reported as being 70% or more male. can be detected in a significant subset of EoE patients using a Our study is unique in that we prospectively recruited control simple technique that can be readily implemented by radiology subjects and deliberately selected males given the demograph- departments. Establishing normal values for esophageal diam- ics of the disease. We also measured maximal diameter at three eter using contrast radiology has the potential to improve the different sites along the esophagus because we were interested in diagnostic efficacy of barium X-rays in this and other esopha - picking up diffuse rather than focal narrowing. Furthermore, we geal disorders. deployed a radiopaque ruler superimposed over the esophagus in order to improve the accuracy of our diameter measurements. Acknowledgements EoE patients typically present with a mechanical type dys- phagia and food bolus obstructions even when there is no obvi- The authors would like to thank Wilma Hopman for her assistance ous endoscopic or barium X-ray abnormality. Although motor with statistical analysis. Supported by a grant from the Physicians abnormalities have been described in EoE (9), the nature of the Services Incorporated Foundation of Ontario, Canada. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy022/5003195 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 5 5. Zimmerman SL, Levine MS, Rubesin SE, et al. Idiopathic eosin- Conflicts of Interest ophilic esophagitis in adults: The ringed esophagus. Radiology Authors have no conflicts of interest to declare. 2005;236:159–165. 6. W hite SB, Levine MS, Rubesin SE, Spencer GS, Katzka DA, Laufer References I. The small-caliber esophagus: Radiographic sign of idiopathic 1. Croese J, Fairley SK, Masson JW, et al. Clinical and endoscopic eosinophilic esophagitis. Radiology 2010; 256(1):127–34. features of eosinophilic esophagitis in adults. Gastrointest Endosc 7. Lee J, Huprich J, Kujath C, et al. Esophageal diameter is decreased 2003;58:516–22. in some patients with eosinophilic esophagitis and might increase 2. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: with topical corticosteroid therapy. Clin Gastroenterol Hepatol Updated consensus recommendations for children and adults. J 2012; 10:481–6. Allergy Clin Immunol 2011;128:3–20. 8. Grudell ABM, Alexander JA, Enders FB, et al. Validation of the 3. Kim HP, Vance RB, Shaheen NJ, Dellon ES. The prevalence Mayo dysphagia questionnaire. Dis Esoph 2007; 20: 202–5. and diagnostic utility of endoscopic features of eosinophilic 9. Martín Martín L, Santander C, Lopez Martín MC, et al. Esophageal esophagitis: A meta-analysis. Clin Gastroenterol Hepatol motor abnormalities in eosinophilic esophagitis identified by high-res - 2012;10:988–96. olution manometry. J Gastroenterol Hepatol 2011;26: 447–1450. 4. Levine MS, Rubesin SE. History and evolution of the barium 10. Kwiatek MA, Hirano I, Kahrilas PJ, Rothe J, Luger D, Pandolfino swallow for evaluation of the pharynx and esophagus. Dysphagia JE. Mechanical properties of the esophagus in eosinophilic esopha- 2017;32:55–72. gitis. Gastroenterology 2011;140:82–90. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy022/5003195 by Ed 'DeepDyve' Gillespie user on 07 June 2018
Journal of the Canadian Association of Gastroenterology – Oxford University Press
Published: May 24, 2018
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