Eosinophilic Esophagitis beyond Eosinophils - an Emerging Phenomenon Overlapping with Eosinophilic Esophagitis: Collegium Internationale Allergologicum (CIA) Update 2023.

Having long been considered the mainstay in eosinophilic esophagitis (EoE) diagnosis and pathogenesis, the role of eosinophils has been questioned and might be less important than previously thought. It is well known now that EoE is a Th2-mediated disease with many more disease features than eosinophilic infiltration. With more knowledge on EoE, less pronounced phenotypes or nuances of the disease have become apparent. In fact, EoE might be only the tip of the iceberg (and the most extreme phenotype) with several variant forms, at least three, lying on a disease spectrum. Although a common (food induced) pathogenesis has yet to be confirmed, gastroenterologists and allergologists should be aware of these new phenomena in order to further characterize these patients. In the following review, we discuss the pathogenesis of EoE, particularly those mechanisms beyond eosinophilic infiltration of the esophageal mucosa, non-eosinophilic inflammatory cell populations, the new disease entity EoE-like disease, variant forms of EoE, and the recently coined term mast cell esophagitis.

[Lymphocytic " itis", from esophagus to large bowel]. / « ites ¼ lymphocytaires, de l'œsophage au côlon.

Intra-epithelial lymphocytosis is an elementary lesion frequently observed in the gastrointestinal tract, which can be found from the esophagus to the colon. Many conditions of a varied nature (dysimmunitary diseases, drugs, infections…) are associated with intra-epithelial lymphocytosis, and the etiological diagnosis most often requires an anatomo-clinical correlation. The pathologist will have to identify histological lesions associated with intra-epithelial lymphocytosis allowing the diagnosis to be oriented in order to propose appropriate treatment. In this review, the main entities associated with digestive intra-epithelial lymphocytosis will be presented, detailing the key elements allowing their diagnosis.

Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study.

OBJECTIVE: Physicians are increasingly confronted with patients presenting with symptoms of esophageal dysfunction resembling eosinophilic esophagitis (EoE), but absence of significant esophageal eosinophilia. The purpose of this study was to characterize and classify this group of EoE variants. DESIGN: Patients from six EoE-centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm2 (<15/hpf) in esophageal biopsies and absence of gastro-esophageal reflux disease (GERD) were included. Clinical, endoscopic, (immuno)-histological, and molecular features were determined and compared with EoE, GERD, and healthy controls. RESULTS: We included 69 patients with EoE variants. Endoscopic abnormalities were found in 53.6%. We identified three histological subtypes: EoE-like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non-specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed-in contrast to EoE-no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE-typical Th2-response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, we found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE-like (characterized by eotaxin-3 expression), non-specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression). CONCLUSION: All EoE variants are clinically and histologically active conditions despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

BACKGROUND: Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. AIM: To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. METHODS: This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. RESULTS: Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). CONCLUSIONS: Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Non gastro-esophageal reflux disease related esophagitis: an overview with a histologic diagnostic approach.

Several pathological conditions, other than gastro-esophageal reflux disease and its complications, can affect the esophagus. While some of these can present with unspecific lesions (i.e. ulcers and epithelial damage) and require clinico-pathological correlation for diagnosis (i.e. drug-induced esophagitis and corrosive esophagitis) other conditions show distinctive histological lesions which enable the pathologist to reach the diagnosis (i.e. some specific infectious esophagites and Crohn's disease). In this context eosinophilic esophagitis is the condition which has been increasingly studied in the last two decades, while lymphocytic esophagitis, a relatively new entity, still represents an enigma. This overview will focus on and describe histologic lesions which allow pathologists to differentiate between these conditions.

Clinical, endoscopic, and histologic characteristics of lymphocytic esophagitis: a systematic review.

OBJECTIVE: Lymphocytic esophagitis (LyE) is a novel, yet poorly described, clinicopathologic entity. The aim of this systematic review was to characterize the demographic, clinical, endoscopic, and histologic features of LyE in observational studies of adult and pediatric patients. DESIGN: We searched the Embase, MEDLINE, and SCOPUS databases for relevant studies in 2018. Two authors reviewed and extracted data from studies that met the inclusion and exclusion criteria. RESULTS: We identified 20 studies for analysis of demographic, clinical, and endoscopic features of LyE. The mean age ranged from 9 to 67 years. When pooled, there were 231 (52.7%) patients with LyE that were female. The most common presenting symptom was dysphagia reported in 191 (48.8%) patients. On endoscopy, most patients with LyE tended to have abnormal findings (69.0%), which included erosive esophagitis, multiple esophageal rings, linear furrows, and narrow-caliber esophagus. In the 31 studies used to assess the histologic definition, the cut-off number of intraepithelial lymphocytes (IELs) was reported in 16 (51.6%) studies, peripapillary IEL specification in 18 (58.1%) studies, and presence of spongiosis in 6 (19.4%) studies. CONCLUSION: We identified a spectrum of demographic, clinical, and endoscopic findings characteristic of patients with LyE. A consensus on the diagnostic criteria of LyE is required.

How to Approach Lymphocytic Esophagitis.

PURPOSE OF REVIEW: Lymphocytic esophagitis (LE) is an unusual esophageal condition defined by an increased number of lymphocytes in the esophageal epithelium. With few published studies of LE available, it is unclear whether LE is a truly distinct clinical entity or a histological manifestation of other known gastrointestinal disorders. This review summarizes recent studies of lymphocytic esophagitis. RECENT FINDINGS: Studies have suggested that LE may be related to eosinophilic esophagitis (EoE) or a manifestation of gastroesophageal reflux disease (GERD). There is an association between LE and Crohn's disease in children, but not in adults. Patients with LE frequently report symptoms of dysphagia and GERD. Treatment options for LE are limited and involve symptom management similar to treatment of EoE or GERD, including proton pump inhibitors (PPI), swallowed topical steroids, and endoscopic dilation. With no formal definition and a variety of clinical presentations and endoscopic findings, diagnosis and management of symptomatic LE patients is challenging for clinicians.

A Japanese case of lymphocytic esophagitis.

We report the case of a 68-year-old Japanese man diagnosed with lymphocytic esophagitis (LE), a rare disease associated with refractory dysphagia. He has had severe dysphagia and heartburn since 2007. Findings of esophagogastroduodenoscopy (EGD) carried out by a local physician in 2010 showed pale mucosa with white exudate and lateral furrows in the esophagus. He was referred to Tohoku University Hospital in 2012, because the symptoms did not improve, despite regular use of a proton pump inhibitor (PPI). At that time, EGD revealed the coexistence of a slight stricture in the upper esophagus, the histopathological findings of which included a predominantly peri-papillary distribution of abundant, infiltrating CD3+ /CD4+ /CD8+ /CD20- lymphocytes without any granulocytes (CD4+  : CD8+  = 3.3:1). These were consistent with a diagnostic criteria of LE. Thereafter, severe dysphagia with food impaction occurred twice a month, despite the long-term use of a PPI, and EGD showed worsened strictures, where endoscopic ultrasonography findings showed marked circumferential thickness of the mucosal and submucosal layers. Then, one session of endoscopic balloon dilatation dramatically improved the dysphagia. Accordingly, LE should be considered an important differential diagnosis of refractory dysphagia based on the characteristic features of endoscopic and pathological findings.

Lymphocytic Esophagitis: A Case Series of Esophageal Disease with Increasing Frequency.

BACKGROUND: Lymphocytic esophagitis (LE) is a poorly understood clinical finding that has been increasingly identified in the last decade. Previous studies proposed increased frequency of LE in elderly females, as well as associations with smoking and pediatric Crohn's disease. OBJECTIVE: We aimed to determine the patient characteristics and clinical features of our adult LE patients. As inflammation in the esophagus has been linked to cancer, this review also describes this association. However, there are no reported cases of malignant transformation in those with underlying lymphocytic esophagitis. METHODS: We retrospectively reviewed records for patients at the University of Missouri Hospital- Columbia (located in the USA) who had a histopathological diagnosis of LE. Cases of LE were identified using the pathology reporting system at the University of Missouri Hospital for esophageal biopsy specimens for the above-mentioned period. RESULTS: The data of a total of 20 adult cases with esophageal biopsy specimens consistent with LE were included. CONCLUSION: LE seems to be a benign but disturbing clinical problem and should be remembered in elderly females complaining of dysphagia or refractory reflux symptoms. It has similar endoscopic findings of eosinophilic esophagitis with rings and esophagitis. Smoking and hiatal hernia are common risk factors. The majority of LE patients can respond to proton pump inhibitor (PPI) therapy. Endoscopic dilations and steroid therapy should be considered for PPI nonresponder LE patients.

Lymphocytic Esophagitis Presenting With Food Impaction.

Lymphocytic esophagitis (LyE) is a rare diagnosis made on esophageal biopsy whose pathogenesis is poorly understood. Since its appearance in the literature 15 years ago, it still remains an enigma due to its low prevalence. In this case report, a 71-year-old male presented with an episode of acute dysphagia due to food impaction. Urgent endoscopy was performed to fragment the food bolus. Repeat endoscopy showed a stricture, and lymphocytic esophagitis was found on esophageal biopsy. A proton pump inhibitor (PPI) was initiated with symptomatic improvement. With its increasing prevalence, lymphocytic esophagitis should be on the differential for causes of dysphagia.

Non eosinophilic chronic stricturing esophagitis: Lessons from thirty eight cases.

BACKGROUND AND AIMS: The endoscopic workup of dysphagia can lead to the diagnosis of atypical esophagitis, with thickened esophageal mucosa, strictures, mucosal exudates, furrows, and sloughing. While these aspects suggest eosinophilic esophagitis, pathology might not report the presence of eosinophils, but rather chronic inflammation, with spongiosis, parakeratosis, and lymphocytic infiltrate. We aimed to report the management of this disease and assess the prevalence of associated dermatological conditions. METHODS: We retrospectively evaluated the medical records of our patients with non-eosinophilic stricturing esophagitis for clinical, endoscopy, and pathology data. Patients were evaluated by a dermatologist. A blood immunoassay and skin biopsy were performed if needed. RESULTS: Thirty-eight patients (twenty-six women) were included in the study. The median age at onset of symptoms was 56.5 years, with a median duration of symptoms of two years. Thirty-five patients presented with dysphagia at diagnosis and eighteen with weight loss. At endoscopy, a single esophageal stenosis was diagnosed in 19 patients, localized in the upper third in 22 patients. Thirty patients received endoscopic treatment (dilatation in 29/38 and local triamcinolone injection in 11/38 patients). In 21 patients, oral, skin or vulvo-anal lesions were found on dermatological examination. Nineteen patients received systemic treatment, including corticosteroids, immunosuppressive drugs and plasmapheresis. Five patients developed esophageal squamous cell carcinoma. CONCLUSION: The management of non-eosinophilic chronic stricturing esophagitis is challenging, because of a low contribution of esophageal biopsies and the refractory nature of the strictures. In our experience, a dermatological evaluation helped in 55% of cases to introduce a systemic treatment, leading to limit the use of endoscopic dilatation. Endoscopic follow-up is needed, considering the significant risk of esophageal squamous cell carcinoma.

Immune Checkpoint Inhibitor-Induced Lymphocytic Esophagitis.

Immune checkpoint inhibitors (ICIs) have emerged as effective treatments for a wide variety of advanced malignancies. However, their use is associated with numerous immune-related toxicities, including within the gastrointestinal tract. We present a rare case of checkpoint inhibitor-induced lymphocytic esophagitis. A 79-year-old male with a past medical history significant for metastatic renal clear cell carcinoma on nivolumab presented to the hospital with dysphagia and symptomatic choledocholithiasis. The patient underwent endoscopic retrograde cholangiopancreatography (ERCP) for the extraction of stones and esophagogastroduodenoscopy (EGD) for dysphagia, which showed esophagitis. Biopsies revealed lymphocytic infiltration of the epithelium, dyskeratotic keratinocytes, and acanthosis, raising suspicion for nivolumab-associated lymphocytic esophagitis. Treatment includes proton pump inhibitors and steroids; however, efficacy is not well described due to the rarity of the condition.

Lymphocytic Esophagitis: Diagnosis and Management in the Emergency Department vs Initial Suspicion of Eosinophilic Esophagitis.

Lymphocytic esophagitis is an increasingly prevalent yet poorly understood condition that is highly disruptive to daily living. The presentation often includes dysphagia, but dysarthria and narrowing of the esophageal lumen may be seen as well. In this case, a 66-year-old female presented to the Emergency Department complaining of dysphagia for several weeks in addition to associated discomfort with the loss of ability to swallow solid foods.

Mixed lymphocytic and collagenous inflammation of the entire gastrointestinal tract under therapy with serotonin and norepinephrine reuptake inhibitors.

Drug-induced injury to the gastrointestinal tract has gained growing significance in recent years, and the list of causative medications keeps expanding. Herein, we present the case of a 45-year-old female with major depressive disorder treated with two serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine). She developed nausea and weight loss. Endoscopic evaluation of the upper and lower gastrointestinal tract rendered grossly normal mucosa in all segments. Histological examination, however, revealed lymphocytic esophagitis, collagenous gastritis, celiac disease-like intraepithelial lymphocytosis of the duodenum, and incomplete collagenous colitis. Gastrointestinal side effects of psychoactive drugs are largely underrecognized. This is the first report of a mixed lymphocytic and collagenous pattern of injury affecting esophagus, stomach, duodenum, and colon triggered by combined treatment with venlafaxine and duloxetine. In patients with unclear symptoms, obtaining biopsies from mucosa that is normal upon endoscopic inspection may render decisive clues for clinical management.

A case of lymphocytic esophagitis in a woman with multiple allergies.

BACKGROUND: Lymphocytic esophagitis is a newly recognized entity of unknown origin. Dysphagia is defined as difficulty swallowing and represents a common symptom in the general population with a prevalence of approximately 20%. Chronic inflammation of the esophageal wall may manifest itself clinically and endoscopically, mimicking inflammation of another origin. However, little is known about the pathogenesis of the disease, as patients are seldom suspected and rarely diagnosed with lymphocytic esophagitis. CASE PRESENTATION: Here, we present a rare case of lymphocytic esophagitis in a patient with multiple allergies and suspected eosinophilic esophagitis. A 28-year-old woman with polyvalent sensitization to food and inhalant allergens presented with intermittent dysphagia, a sensation of a foreign body in the throat, itchiness of the oral cavity after ingesting certain foods, heartburn, and prolonged chewing time. A skin prick test showed positive results for birch-tree, alder, hazel, and rye pollen, as well as house dust mites. Apart from obesity (BMI 30 kg/m2), multiple pustules and excoriations on the skin, her physical examination was insignificant. Esophagogastroduodenoscopy (EGD) was performed revealing full-length but discrete trachealization of the esophagus. A barium swallow test showed slowing of esophageal peristalsis in the recumbent position. No esophageal pathology was observed. A histopathological analysis of mucosal samples revealed slight hyperplasia of the basal layer of the esophagus, and the stomach showed changes typical of chronic gastritis. CONCLUSIONS: In summary, this clinical case illustrates that lymphocytic esophagitis, as a newly recognized entity, should be considered in the differential diagnosis of chronic dysphagia. Additionally, when treating allergic patients, clinicians should be aware that lymphocytic esophagitis, distinct from eosinophilic esophagitis, should be considered in the diagnosis of patients with atopy and upper gastrointestinal symptoms.

Histologic Findings in Mucosa and Muscularis Propria Biopsied During Peroral Endoscopic Myotomy in Patients With Achalasia.

BACKGROUND: Peroral endoscopic myotomy (POEM) has been increasingly used to treat achalasia. Previous studies have reported high frequency of muscular eosinophilic infiltration in achalasia. Esophageal mucosal changes in achalasia have only been studied in esophagectomy specimens. Cardia mucosal changes in achalasia have not been reported previously. We aimed to further characterize the esophageal, gastric cardia, and muscularis propria changes in achalasia. METHODS: This was a pilot study. Patients with clinically and radiographically confirmed achalasia who underwent POEM were enrolled in the study. Mucosal biopsies were taken 1 cm proximal and 1 cm distal to the gastroesophageal junction, and muscularis propria biopsies were taken from the mid esophagus. Tissues were submitted for histological evaluation. RESULTS: Eighteen patients (10 male and eight female, mean age: 60.7 (standard deviation (SD): 13) years) were enrolled in this pilot study. Nine patients had type II achalasia, two type III, one type I, five esophageal gastric outlet obstruction, and one unspecific type achalasia. The mean duration of symptoms prior to POEM was 79 (range 1 - 480) months. All patients had a dilated esophagus on examination, but no endoscopic evidence of Barrett's esophagus. Esophageal, gastric cardia, and muscular biopsies were performed in 17, 13, and 17 patients, respectively. Basal hyperplasia, spongiosis, ballooning, and parakeratosis were seen in 92.3%, 100%, 100%, and 76.5% of cases, respectively. Intraepithelial lymphocytosis was seen in 70.5% of cases, and active esophagitis was seen in 23.5% of case. Six (35.3%) cases had few intraepithelial eosinophils, but none of them had > 15 eosinophils per high power field. Histologic findings in gastric cardia mucosa included carditis (69.2%), H. pylori gastritis (7.6%), and reactive gastropathy (15.4%). One case (7.6%) showed low-grade dysplasia arising from intestinal metaplasia in the cardia. Absence of ganglion cells in the muscular biopsies was noted in 88.2% of cases, and the remaining two showed rare residual ganglion cells with ganglionitis in one case (5.8%). Muscular atrophy and interstitial fibrosis were observed in 52.9% and 82.3% of the cases, respectively. Two cases (11.7%) had eosinophilic inflammation in the muscularis propria and one of them was accompanied by lymphocytic inflammation. CONCLUSIONS: Muscular biopsies in our study revealed loss of ganglion cells, supporting the view that achalasia is a primary esophageal disease with ganglion cell depletion. Squamous mucosa in achalasia showed changes mimicking reflux and lymphocytic esophagitis. Cardia mucosa in achalasia patients often were inflamed and uncommonly showed intestinal metaplasia and glandular dysplasia.

Lymphocytic Esophagitis With Predominance of CD4 T Cells and Expansion of Th1 Cells Is Associated With Achalasia.

OBJECTIVES: Although histologic features in biopsies suggesting a possibility of achalasia would be helpful diagnostically, such features remain unknown. The goal of this study was to explore the prevalence, histologic features, and immunophenotype of lymphocytic esophagitis (LyE) in achalasia biopsies. METHODS: The study group consisted of 57 patients with achalasia. Controls comprised 52 patients with severe gastroesophageal reflux disease (GERD) and normal esophageal motility. CD4/CD8 immunophenotype of lymphocytes was analyzed by immunohistochemistry. RESULTS: LyE was identified in 30% (17/57) of patients with achalasia and 6% (3/52) of patients with GERD, indicating a strong association with achalasia (odds ratio, 6.94; 95% confidence interval, 1.90-25.38). LyE was focal in 59% (10/17) of the cases and diffuse in 41% (7/17). CD4 T-cell predominance over CD8 T cells was observed in 88% of patients with achalasia and LyE. T helper 1 (Th1) cells, but not T helper 2 cells, were expanded in CD4 T cells; in the absence of evident infection, this was compatible with the role of Th1 cells in organ-specific autoimmunity. CONCLUSIONS: Achalasia should be considered in the differential diagnosis of clinical entities associated with CD4-predominant LyE. Additional studies to explore the significance of Th1 cells in achalasia-associated LyE are warranted.

Inflammatory conditions of the esophagus: an update.

A variety of inflammatory disorders involve the esophagus. This commentary discusses the pathology of some forms of esophagitis, with an emphasis on recent developments. The initial section focuses on some common forms of nonreflux esophagitis, including lymphocytic esophagitis and eosinophilic esophagitis. Recent studies suggest that lymphocytic esophagitis may be associated with esophageal motility disorders and gastroesophageal reflux disease. Immunophenotypic features of intraepithelial lymphocytes may be helpful in distinguishing these conditions. Updates on the criteria and the limitations of histologic approach to the diagnosis of eosinophilic esophagitis are presented and new diagnostic adjuncts are discussed. In the remaining section, novel entities, such as IgG4-related esophagitis, are discussed. IgG4-related esophagitis has been recognized as a cause of esophageal lymphoplasmacytic inflammation. Increased understanding of esophageal inflammation remains an important goal that likely will lead to new approaches in the therapy of inflammatory esophageal diseases.

Lymphocytic esophagitis: An Australian (Queensland) case series of a newly recognized mimic of eosinophilic esophagitis.

BACKGROUND AND AIM: Lymphocytic esophagitis (LoE) is a recently described upper gastrointestinal tract "disorder" diagnosis of which hinges on histology and is characterized by the excessive infiltration of lymphocytes in the peripapillary fields of the esophageal epithelium, with clinical manifestations similar to those of eosinophilic esophagitis (EoE). In this article, we aim to describe for the first time the clinico-pathological characteristics of a large cohort of Australian (Queensland) cases of LoE. METHODS: Histological data that fulfilled the criteria (predominant lymphocytic infiltration in the peripapillary fields, none or minimal neutrophils or eosinophils, and no infection) were collected between January 2014 and May 2016 from a number of major Queensland Public Hospital anatomical pathology laboratories. Patient presentations were subsequently examined to compile clinical and endoscopic correlates. RESULTS: A total of 62 cases of LoE were identified. The median age was 55 years, with 59.6% of subjects being male. Major clinical manifestations included dysphagia (32), epigastric or abdominal pain (8), gastro-esophageal reflux (8), association with Crohn's disease (8), and vomiting or diarrhea (6). Endoscopy was normal in 47% of cases; 47% had appearances similar to those of EoE. There were three cases with associated mild monilial esophagitis (6%). CONCLUSION: LoE is a relatively recently recognized condition of the esophagus with variable clinical and endoscopic findings. Diagnosis is based on characteristic histological features. Further investigation is needed to ascertain the etiopathology and natural history of the condition and to establish a safe and effective treatment regimen.

[Emerging Issues in Esophageal Motility Diseases].

With the advances in technology and medical knowledge, new diseases are being identified and investigated. Esophageal motility disorders have been re-defined using high-resolution manometry and their pathogenesis are being better understood. The use of opioid analgesics is increasing worldwide, particularly in the United States, but their chronic use can cause opioid-induced esophageal dysfunction, which mimics spastic motor disorders, including achalasia type 3 or 2 and esophagogastric junction outflow obstruction. Eosinophilic esophagitis is identified by eosinophilic infiltration confirmed on a pathological examination. The condition is often associated with esophageal motility abnormalities. On the other hand, recent studies have suggested that muscle-predominant eosinophilic infiltration, eosinophilic esophageal myositis, might manifest as spastic motor disorders, including achalasia or jackhammer esophagus. Lymphocytic esophagitis is an unusual esophageal condition, which is confirmed by the increased number of lymphocytes in the esophageal epithelium. Although several reports have supported the existence of lymphocytic esophagitis, it is still unclear whether lymphocytic esophagitis is a distinct disease entity or another spectrum of other esophageal diseases, such as gastroesophageal reflux disease or eosinophilic esophagitis. This review presents evidence and reports on the emerging issues in esophageal motility disorders, including opioid-induced esophageal dysfunction, eosinophilic esophagitis with eosinophilic esophageal myositis, and lymphocytic esophagitis.