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Eosinophilic esophagitis (EoE) is a chronic immune mediated clinico-pathologic disease characterized by esophageal dysfunction (J Allergy Clin Immunol 2011;128:3–20 e6). In adolescents and adults, the clinical manifestations of EoE can often be attributed to chronic inflammation resulting in esophageal luminal narrowing or focal stricture (Gastrointest Endosc 2014;79:577–85 e4; Am J Physiol Gastrointest Liver Physiol 2012;303(11):G1175–87; Gastroenterol Clin North Am 2014;43:297–316). EoE is now recognized as a leading cause of dysphagia and food impactions in adults (Gastrointest Endosc 2005;61:795–801). However, there are no validated measures that quantify the degree of fibrosis in EoE. One potential method would be endoscopic evaluation. In order to establish a nomenclature for the endoscopic description of EoE, Hirano et al developed and validated the Endoscopic Reference Score (EREFS classification system) (Gut 2013;62:489–95). Another method is the functional luminal imaging probe (EndoFLIP), a novel technology that uses high resolution impedance planimetry to evaluate hollow organ distention (Gastroenterology 2011;140:82–90; Clin Gastroenterol Hepatol 2013;11:1101–1107 e1). However, the relation between endoscopic findings of EoE and esophageal distention as quantified by EndoFLIP has yet to be assessed.
In this context, the study by Chen et al extends the role of EndoFLIP technology in EoE. The authors aimed to evaluate the association between endoscopic severity in EoE patients, as measured by EREFS, and esophageal distensibility, as measured by EndoFLIP. They prospectively recruited 72 adults with symptoms of esophageal dysfunction and pathology confirming EoE. At the time of the study, 90% of patients reported dysphagia. The patients underwent an upper endoscopy with biopsies and an EREFS score was assigned. During the same endoscopy, the EndoFLIP was used to measure esophageal distensibility.
There are several notable findings. They report that the presence of severe (grade 3) rings were associated with 58% lower esophageal distensibility and all of those with severe rings had a history of food impactions. Interestingly, there was no association between distensibility and the severity of exudates and furrows. There was a correlation between mean and distal eosinophil counts and the severity of exudates and furrows, both typically considered to be inflammatory findings of EoE. There was no correlation between esophageal eosinophil counts and rings. They also did not find an association between esophageal eosinophilia and the degree of distensibility.
The authors conclude that the use of rings on endoscopic evaluation could be considered as a marker for not only esophageal remodeling in EoE, but for decreased distensibility and increased risk for food impactions. Therefore, rings may be the endoscopic finding with the most clinical relevance. In contrast, their data on esophageal eosinophil counts indicate a potential dissociation between inflammation and tissue remodeling.
The clinical symptoms of eosinophilic esophagitis vary widely (J Allergy Clin Immunol 2011;128:3–20 e6; Expert Rev Gastroenterol Hepatol 2014;8:925–34; Am J Gastroenterol 2013;108:679–92; Gastroenterology 2014;147:1238–54). Adolescents and adults often present with dysphagia and food impactions (Am J Gastroenterol 2007;102:2300–13; Clin Gastroenterol Hepatol 2005;3:1198–206; Am J Gastroenterol 2007;102:2627–32; Clin Gastroenterol Hepatol 2009;7:420–6, e1–2), but symptoms may not always be reliable as patients can minimize symptoms with dietary and behavioral modifications (Gastroenterol Clin North Am 2013;42:133–53; Gastroenterology 2014;147:1255–66 e21). Some patients may also present with heartburn symptoms refractory to proton-pump inhibitors (Clin Gastroenterol Hepatol 2005;3:1198–206; Clin Gastroenterol Hepatol 2009;7:420–6, e1–2; Dig Dis Sci 2010;55:28–31; Dig Liver Dis 2011;43:204–8), and symptoms alone are not specific for EoE. Similarly, while histopathology that reveals at least 15 eosinophils per high power field is suggestive of EoE (J Allergy Clin Immunol 2011;128:3–20 e6), this is also not specific for EoE (J Allergy Clin Immunol 2011;128:3–20 e6; Am J Gastroenterol 2013;108:679–92; Am J Gastroenterol 2008;103:435–42). Upper endoscopy is required to obtain esophageal biopsies and to assess for other causes of the patient’s symptoms. During this procedure, the typical features of EoE can also be assessed and may provide a visual sense of mucosal involvement in order to monitor the disease over time. These findings, however, have previously been considered to not have high enough sensitivity, specificity and predictive value to be diagnostic, and there was substantial variability in how findings were recorded (Gastroenterol Clin North Am 2013;42:133–53; Clin Gastroenterol Hepatol 2012;10:988–96 e5).
To address this variability in reporting of endoscopic findings of EoE, Hirano and colleagues developed and validated the EREFS classification (Gut 2013;62:489–95). This consists of the five most common and reproducibly identified findings including edema (or decreased vascularity), rings, exudates (or white plaques), furrows, and strictures. EREFS has now been validated in both the United States and Europe (Endoscopy 2014;46:1049–55). It has also been correlated with histologic findings of eosinophilic esophagitis (Neurogastroenterol Motil 2016; epub; Clin Gastroenterol Hepatol 2016;14:31–9), and has been shown to have utility in diagnosing and monitoring treatment response in EoE (Clin Gastroenterol Hepatol 2016;14:31–9). Therefore it should be used in standard clinical practice, as well as in research, to quantify the severity of EoE endoscopic findings (Endoscopy 2014;46:1043–5).
Despite the strides made in assessing EoE, we are still limited to observing the surface features of the esophageal mucosa with current endoscopic and histologic techniques and do not obtain a transmural view of the esophagus. This is important as there are data suggesting that inflammation and fibrosis in EoE can be transmural, and that involvement of the entire esophageal wall in the disease process may be related to ongoing clinical symptoms (Gastroenterol Clin North Am 2014;43:297–316; Ann Gastroenterol 2013;26:166–169; Dis Esophagus 2011;24:E11–5; J Allergy Clin Immunol 2012;130:798–800; Gastroenterology 2014;146:1266–77 e1–9; Gastrointest Endosc 2003;57:30–6).
The recent application of EndoFLIP technology in EoE is a potential solution, as esophageal distention is a promising marker for transmural assessment of the esophagus. EndoFLIP is a novel technique that uses high resolution impedance planimetry to determine regional variations in pressure in a cross-sectional area of a hollow organ, such as the esophagus (Therap Adv Gastroenterol 2013;6:97–107). It has been used to investigate the esophagogastric junction in various esophageal conditions, such as gastroesophageal reflux disease (GERD), achalasia and after esophageal surgeries (Gastroenterology 2011;140:82–90). More recently, endoFLIP has been used to study EoE. Kwiatek and colleagues showed that the esophagus is less distensible in eosinophilic esophagitis than in control patients without EoE (Gastroenterology 2011;140:82–90; Therap Adv Gastroenterol 2013;6:97–107). Nicodeme and colleagues extended this work to show that the decreased distensibility was also important clinically; even among EoE patients, those with the lowest distensibility were most likely to have future food impactions (Clin Gastroenterol Hepatol 2013;11:1101–1107 e1), and decreased esophageal distention may be in the causal pathway of food impactions (J Neurogastroenterol Motil 2012;18:357–64).
While a measure of esophageal distensibility is important in assessing EoE and EndoFLIP technology can provide a global assessment of esophageal distensibility (Therap Adv Gastroenterol 2013;6:97–107; Gastrointest Endosc 2010;72:272–8; Dig Dis 2014;32:78–83), it still has some limitations. For example, its use in EoE is primarily still in research, rather than clinical, applications. The device itself is also not commonly used in clinical GI practice, so it is unlikely to be found outside of tertiary academic settings. Therefore, if there were a simple to measure, but objective, proxy for esophageal distensibility and transmural modeling, this would be extremely valuable.
The study by Chen et al potentially provides such a measure. In their careful analysis of the relationship between the EREFS score and esophageal distensibility as measured by the EndoFLIP, they showed that increasing severity of the fibrotic finding of esophageal rings, but not inflammatory findings of exudates or furrows was strongly associated with decreasing esophageal distensibility. This has important clinical implications. First, it further supports use of the EREFS classification. Second, it provides prognostic implications regarding one of the EREFS components – esophageal rings. Third, it shows that severity of esophageal rings can be a simple marker for esophageal remodeling. Finally, this marker is correlated with a key clinical outcome – food impaction – that can lead to substantial morbidity and costs related to EoE (Aliment Pharmacol Ther 2015;42:91–8; J Clin Gastroenterol 2007;41:356–61; Am J Gastroenterol 2015;110:626–32). Thus, widespread use of the Endoscopic Reference Score for EoE patients undergoing upper endoscopy for known or suspected EoE is important. Providers should be cognizant of the impact of fibrostenotic remodeling changes on the clinical presentation and prognosis of EoE. Further work could assess whether a decrease in rings after treatment also correlates with improved distensibility and whether the same relationship is observed with dysphagia, focal strictures and mucosal fragility.