AGA Clinical Practice Update on Esophageal Dysfunction Due to Disordered Immunity and Infection: Expert Review.

METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. DESCRIPTION: Infectious and immune-mediated esophageal disorders are poorly understood and often under-diagnosed conditions that lead to esophageal dysfunction and health care costs due to repeated procedures and a lack of understanding of their etiology and pathogenesis. Without a high index of suspicion, these disorders may be overlooked. Esophageal dysfunction may arise from active, localized infection and immune-mediated disease (ie, candida, etc.) or from an organ-specific manifestation of a more diffuse immune-mediated disease or infection (ie, systemic sclerosis, connective tissue disease, neurologic disease). These conditions can sometimes lead to neuromuscular dysfunction and subsequent esophageal dysmotility. Awareness of local and systemic processes that lead to esophageal dysfunction will improve patient outcomes by focusing therapeutics and limiting unnecessary procedures. Therefore, the purpose of this AGA Clinical Practice Update Expert Review is to provide BPA on diagnostic considerations of immune-mediated disorders that should be considered when encountering patients with dysphagia, heartburn, and odynophagia. Best Practice Advice Statements: BEST PRACTICE ADVICE 1: Gastroenterologists should be aware of the esophageal manifestations of systemic immunologic and infectious diseases to reduce diagnostic delay. Clinicians should identify if there are risks for inflammatory or infectious possibilities for a patient's esophageal symptoms and investigate for these disorders as a potential cause of esophageal dysfunction. BEST PRACTICE ADVICE 2: Once esophageal infection is identified, clinicians should identify whether accompanying signs/symptoms suggest immunocompromise leading to a more systemic infection. Consultation with an infectious disease expert will aid in guiding appropriate treatment. BEST PRACTICE ADVICE 3: If symptoms do not improve after therapy for infectious esophagitis, evaluation for refractory infection or additional underlying sources of esophageal and immunologic dysfunction should be performed. BEST PRACTICE ADVICE 4: In individuals with eosinophilic esophagitis (EoE) who continue to experience symptoms of esophageal dysfunction despite histologic and endoscopic disease remission, clinicians should be aware that some patients with EoE may develop motility disorders. Further evaluation of esophageal motility may be warranted. BEST PRACTICE ADVICE 5: In individuals with histologic and endoscopic features of lymphocytic esophagitis, clinicians should consider treatment of lymphocytic-related inflammation with proton-pump inhibitor therapy or swallowed topical corticosteroids and as needed esophageal dilation. BEST PRACTICE ADVICE 6: In patients who present with esophageal symptoms in the setting of hypereosinophilia (absolute eosinophil count [AEC] >1500 cells/uL), consider further work-up of non-EoE eosinophilic gastrointestinal (GI) disease, hypereosinophilic syndrome, and eosinophilic granulomatosis with polyangiitis (EGPA). Consultation with allergy/immunology may help guide further diagnostic work-up and treatment. BEST PRACTICE ADVICE 7: In individuals with rheumatologic diseases of systemic sclerosis (SSc), mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), or Sjogren's disease, clinicians should be aware that esophageal symptoms can occur due to involvement of the esophageal muscle layer, resulting in dysmotility and/or incompetence of the lower esophageal sphincter. The degree of dysfunction is often especially significant in those with SSc or MCTD. BEST PRACTICE ADVICE 8: In individuals with Crohn's disease, clinicians should be aware that a minority of individuals can develop esophageal involvement from inflammatory, stricturing, or fistulizing changes with granulomas seen histologically. Esophageal manifestations of Crohn's disease tend to occur in individuals with active intestinal disease. BEST PRACTICE ADVICE 9: In individuals with dermatologic diseases of lichen planus or bullous disorders, clinicians should be aware that dysphagia can occur due to endoscopically visible esophageal mucosal involvement. Esophageal lichen planus, in particular, can occur without skin involvement and can be difficult to define on esophageal histopathology. BEST PRACTICE ADVICE 10: Clinicians should consider infectious and inflammatory causes of secondary achalasia during initial evaluation. One should query for any history of recent COVID infections, risks for Chagas disease, and symptoms or signs of eosinophilic disease.

An endoscopic scoring system for achalasia: the CARS score.

BACKGROUND AND AIMS: The diagnosis of achalasia is associated with an average delay of 2 years. Endoscopic features may prompt an earlier diagnosis. We aimed to develop and test a novel endoscopic score, CARS, for the prediction of achalasia. METHODS: Part 1: Twenty endoscopic videos were taken from patients undergoing endoscopy for dysphagia or reflux. A survey with videos and endoscopic criteria options was distributed to 6 esophagologists and 6 general gastroenterologists. Inter-rater reliability (IRR) was measured and logistic regression was used to evaluate predictive performance. Three rounds of review were conducted to select the final score of 4 components. Part 2: A retrospective review was conducted for consecutive patients who had comprehensive esophageal testing. Each patient had a CARS endoscopic score calculated based on findings reported at endoscopy. RESULTS: From a video review and analysis of score components, IRR ranged from 0.23 to 0.57 for score components. The final CARS score was selected based on the following 4 components: Contents, Anatomy, Resistance, and Stasis. In a mixed-effects model, the mean score across raters was higher for achalasia compared with nonachalasia subjects (4.44 vs 0.87; P < .01). In part 2 of the study, achalasia patients had a higher mean CARS score compared with those with no or ineffective motility disorder (mean 4.1 vs 1.3; P < .01). CONCLUSIONS: We developed a CARS score based on reliability performance in a video-based survey and tested the score in a clinical setting. The CARS score performed well in predicting achalasia.

Frequent discrepancies among diagnostic tests for detecting lower esophageal sphincter-related obstruction.

BACKGROUND: There are frequent discrepancies among high-resolution manometry (HRM), functional lumen imaging probe (FLIP), and esophagram in identifying lower esophageal sphincter (LES)-related obstruction. We aimed to determine the frequency of those discrepancies and how they influenced clinical treatment/outcomes. METHODS: We identified patients who had all three tests (HRM, FLIP, and esophagram) and endoscopy performed for evaluation of esophageal symptoms in our Center for Esophageal Diseases. Discrepancies among the tests for the presence of LES obstruction were noted, and the performance of individual tests was compared against a consensus opinion rendered by a panel of esophagologists. Binary logistical regression was performed, and ROC curves were generated for prediction of the consensus clinical diagnosis of LES obstruction. KEY RESULTS: A total of 126 patients (mean age 57.9 ± 17.0 years; 67% female) met inclusion criteria. All three tests agreed on the presence or absence of LES obstruction in only 72 (57%) patients [no LES obstruction in 57 (45%), LES obstruction in 15 (12%)]. Thirteen patients (10%) had a change in management based on additional findings on FLIP +/- esophagram not seen on HRM with 69% having symptomatic improvement after LES-directed intervention. FLIP was the strongest predictor of a consensus diagnosis of LES obstruction by logistic regression and ROC (OR 23.36, AUC 0.796), followed by HRM (OR 15.41, AUC 0.764). CONCLUSIONS & INFERENCE: High-resolution manometry, functional lumen imaging probe, and esophagram each have considerable limitations for identifying LES obstruction, and discrepancies among these tests occur frequently. Multimodal testing is often required for adequate evaluation of LES-related obstruction.

Yield of Repeat Endoscopy for Barrett's Esophagus After Normal Index Endoscopy.

INTRODUCTION: Guidelines suggest 1-time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at an increased risk of esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals after a normal index EGD. METHODS: We conducted a national retrospective analysis within the U S Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC, or esophagogastric junction adenocarcinoma (EGJAC) and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC. RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years after an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of them, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC after the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. A longer duration between EGD was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years 1.31; 95% confidence interval [CI] 1.19-1.44), particularly among those who were younger during the index EGD (ages 19-29 years: aOR 3.92; 95% CI 1.24-12.4; ages 60-69 years: aOR 1.19; 95% CI 1.01-1.40). DISCUSSION: The yield of repeat EGD for BE/EAC/EGJAC seems to increase with time after a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

Impact of gastroesophageal reflux disease on idiopathic pulmonary fibrosis and lung transplant recipients.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is a prevalent subset of interstitial lung disease (ILD) that often progresses to require lung transplantation. Gastroesophageal reflux disease (GERD) is common in the IPF population, and GER-related micro-aspiration appears to be an important risk factor for IPF pathogenesis and for the deterioration of transplanted lung function. RECENT FINDINGS: Many patients with IPF have elevated esophageal acid exposure on reflux testing despite having no or minimal symptoms. Studies on the effects of medical GERD therapy on IPF-related outcomes have had mixed results. Antireflux surgery is safe in appropriately selected IPF patients, and appears to have potential for slowing the decline of lung function. GERD can persist, improve or develop after lung transplantation, and the presence of GERD is associated with allograft injury and pulmonary function decline in lung transplant recipients. SUMMARY: Clinicians should have a low threshold to assess for objective evidence of GERD in IPF patients. Antireflux surgery in IPF patients with GERD appears to improve lung function, but further studies are needed before surgical treatment can be recommended routinely in this setting. In lung transplant recipients, reflux testing after transplant is the most accurate way to guide GERD treatment decisions.

Spastic secondary contractile patterns identified by FLIP panometry in symptomatic patients with unremarkable high-resolution manometry.

BACKGROUND: Functional lumen imaging probe (FLIP) panometry can show spastic secondary contractile patterns of unclear significance in symptomatic patients who have no esophageal obstructive disorders, and no motility disorders on high-resolution manometry (HRM). METHODS: We retrospectively analyzed non-obstructed, symptomatic patients with HRM findings of no motility disorder or ineffective esophageal motility (IEM) for whom spastic secondary contractile patterns identified by FLIP panometry were used to guide treatment. Symptoms were scored using the Brief Esophageal Dysphagia Questionnaire (BEDQ). KEY RESULTS: We identified ten symptomatic patients treated at our medical center who met inclusion criteria (seven women; mean age 56 years; eight no motility disorder, two IEM). On FLIP panometry, seven had spastic secondary contractions at 60 ml, two at 40 ml, and one at both 40 ml and 60 ml balloon volumes. Eight patients (80%) had improvement in BEDQ scores with therapies that targeted the spastic secondary contractile patterns identified by FLIP (five botulinum toxin injection, two Esoflip dilation, and one Heller myotomy). Interestingly, review of HRM tracings revealed that all patients had a novel HRM finding of mid-vertical pressurization in at least 20% swallows, with seven exhibiting this finding in >50% of swallows. CONCLUSIONS: This case series demonstrates that treatments targeting spastic secondary contractions identified by FLIP panometry can result in symptomatic improvement in patients with no obstructive disorder and no diagnostic motility disorder on HRM. In such patients, we have identified the novel HRM finding of mid-vertical pressurization, which might be the manometric manifestation of spasm limited to the mid-esophagus.

Phenotyping patients with borderline elevated esophageal acid exposure.

Acid exposure time (AET) <4% on ambulatory reflux monitoring definitively rules out pathologic gastroesophageal acid reflux, while AET >6% indicates pathologic reflux per the Lyon Consensus, leaving AET of 4-6% as borderline. We aimed to elucidate the borderline AET population and identify metrics that could help differentiate this group. A total of 50 subjects in each group, AET <4, 4-6, and >6% on pH-impedance monitoring between 2015 and 2019, were retrospectively reviewed. In addition to demographic and clinical information, the extracted data included mean nocturnal baseline impedance (MNBI) on reflux study and high-resolution manometry (HRM) parameters and diagnosis. After excluding patients with prior foregut surgery, major esophageal motility disorder, or unreliable impedance testing, a total of 89 subjects were included in the analysis (25 with normal AET < 4%, 38 with borderline 4-6%, 26 with abnormal >6%). MNBI in borderline AET patients was significantly lower compared to normal AET (1607.7 vs. 2524.0 ohms, P < 0.01), and higher than abnormal AET (951.5 ohms, P < 0.01). Borderline subjects had a greater frequency of ineffective esophageal motility (IEM) diagnosis per Chicago classification v3.0 (42.1 vs. 8.0%, P = 0.01), but did not demonstrate any differences compared to abnormal subjects (34.6%, P = 0.56). Patients with borderline AET had an average MNBI that was in between normal AET and abnormal AET. Borderline AET patients also commonly demonstrate IEM on HRM, similar to those with abnormal AET. Our findings can be potentially useful in assigning higher clinical significance for patients found to have borderline AET with concomitant low MNBI and IEM on manometry.

Long-Term Quality of Life Following Endoscopic Therapy Compared to Esophagectomy for Neoplastic Barrett's Esophagus.

INTRODUCTION: Endoscopic therapy (ET) and esophagectomy result in similar survival for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC), but the long-term quality of life (QOL) has not been compared. AIMS: We aimed to compare long-term QOL between patients who had undergone ET versus esophagectomy. METHODS: Patients were included if they underwent ET or esophagectomy at the University of Michigan since 2000 for the treatment of HGD or T1a EAC. Two validated survey QOL questionnaires were mailed to the patients. We compared QOL between and within groups (ET = 91, esophagectomy = 62), adjusting for covariates. RESULTS: The median time since initial intervention was 6.8 years. Compared to esophagectomy, ET patients tended to be older, had a lower prevalence of EAC, and had a shorter duration since therapy. ET patients had worse adjusted physical and role functioning than esophagectomy patients. However, the adjusted odds ratio (OR) of having symptoms was significantly less with ET for diarrhea (0.287; 95% confidence interval [CI] = 0.114, 0.724), trouble eating (0.207; 0.0766, 0.562), choking (0.325; 0.119, 0.888), coughing (0.291; 0.114, 0.746), and speech difficulty (0.306; 0.0959, 0.978). Amongst the ET patients, we found that the number of therapy sessions and need for dilation were associated with worse outcomes. DISCUSSION: Multiple measures of symptom status were better with ET compared to esophagectomy following treatment of BE with HGD or T1a EAC. We observed worse long-term physical and role functioning in ET patients which could reflect unmeasured baseline functional status rather than a causal effect of ET.

Provider Variability in the Management Patterns of Increased Nonacid Reflux.

INTRODUCTION: Increased nonacid reflux is diagnosed in a subgroup of patients with gastroesophageal reflux disease who often present with reflux symptoms refractory to proton-pump inhibitor therapy. Despite the prevalence of this condition, the management approach for patients with increased nonacid reflux can often be varied and unclear. AIMS: Our primary aim was to investigate physician management patterns for patients who had received a diagnosis of increased nonacid reflux on impedance-pH studies. METHODS: Reflux studies in patients with increased nonacid reflux per Lyon Consensus criteria and management approaches were retrospectively reviewed. Reflux symptom survey, manometry findings, reflux symptom association (RSA) on reflux testing, immediate posttesting management information, and managing provider information were assessed. RESULTS: A total of 43 subjects in total were analyzed. Management plan after a diagnosis of increased nonacid reflux was decided by a gastroenterologist in over 95% of cases and varied greatly with no changes being the most common. Even among subjects with + RSA on reflux monitoring, no change in management was the most common action, although this occurred much less frequently compared to subjects with - RSA (28.6% vs. 78.6%, p < 0.01). When change in therapy occurred, medical treatment with baclofen was the most common choice (21.4%). Other management changes included medications for visceral hypersensitivity and antireflux surgery, although these changes occurred rarely. CONCLUSIONS: Abnormally increased nonacid reflux is frequently encountered on impedance-pH studies; however, management decisions vary significantly among gastroenterologists. When treatment change is implemented, they are variable and can include lifestyle modifications, medication trials, or antireflux surgery. Future development of standardized management algorithms for increased nonacid reflux is needed.

Clinical impact of routine esophagram after peroral endoscopic myotomy.

BACKGROUND AND AIMS: It is unclear whether the common practice of postoperative day (POD) 1 esophagram impacts clinical care or reliably identifies significant adverse events (AEs) related to peroral endoscopic myotomy (POEM). Therefore, we aimed to correlate the most clinically relevant esophagram findings with postoperative outcomes after POEM. METHODS: Patients were retrospectively reviewed and included if they underwent POEM at 1 of the 3 study institutions between 2014 and 2018. Patient outcomes were assessed in relation to relevant POD 1 esophagram findings such as esophageal dissection or leak. RESULTS: One hundred seventy post-POEM contrast esophagrams (139 fluoroscopy-based vs 31 CT-based) performed on POD 1 were included. Most esophagrams (n = 98) contained abnormal findings but only 5 showed esophageal leak or dissection. Confirmed postoperative AEs of leak or dissection occurred in 4 patients. In 2 patients, POD 1 esophagram appropriately identified the leak or dissection, but in the other 2 patients the initial esophagram was negative, and the AEs were not recognized before clinical deterioration. One patient had a false-positive leak and dissection noted on esophagram leading to an unremarkable endoscopy. CONCLUSIONS: Despite the low AE rate after POEM, follow-up esophagram on POD 1 frequently shows expected, unremarkable postprocedural findings and occasionally fails to diagnose serious AEs. This results in pitfalls in accuracy regarding agreement between esophagram versus clinical and endoscopic findings. Relying exclusively on esophagram for post-POEM clinical decision-making can lead to unnecessary additional testing or missed AEs.

Per-oral Endoscopic Myotomy Biopsies of Achalasia Patients Reveal Schwann Cell Depletion in the Muscularis Propria.

Achalasia is a neurodegenerative condition resulting in abnormal lower esophageal sphincter relaxation and impaired upstream esophageal body peristalsis.1 The pathophysiology and natural history of achalasia remain unclear, and evaluation of the histopathogenesis of achalasia has traditionally been challenging because the esophageal wall muscularis propria is not typically accessible via routine endoscopic biopsies.

Nivolumab-induced large-duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab.

Immune checkpoint inhibitor therapy has become a cornerstone in the management of many oncologic diseases. Although it is well tolerated in most patients, a wide spectrum of adverse events has been described as a result of immune system alteration. We present a case of a woman with metastatic bronchogenic adenocarcinoma who was initially thought to have immune-mediated hepatitis, but eventually discovered to have a rarely described immune-mediated cholangiopathy. Her cholangiopathy appeared to stabilize following ursodeoxycholic acid and tocilizumab after several lines of guideline-directed therapy. Awareness of this unique toxicity following immune checkpoint inhibitor, and potential treatment options may help clinicians manage this rare but serious complication.