Clinical Case Summary

Eosinophilic esophagitis is characterized by dysphagia, GERD and impactions. It is related to environmental and genetic factors resulting in an altered Th2 immune response that allows overexposure to circulating antigens.
We present the case of a 46-year-old male with EoE since 2016 and no treatment, who came to the ED for dysphagia, odynophagia and fever. No notable alterations in X-ray, ECG and blood tests. A gastroscopy showed rounded ulcers in distal esophagus with biopsies showing changes compatible with herpetic infection and positive IHC for HSV1. Treatment was started with Acyclovir 10 days + PPI, with disappearance of symptoms and resolution of ulcers in gastroscopy after 8 weeks.
HSV esophagitis is frequent in immunocompromised patients related to viral reactivation. In immunocompetent patients it is infrequent and self-limited manner in most cases.
In recent years, the relationship between EoE and HSV esophagitis has been postulated through three possible hypotheses.
Firstly, inadequately treated EoE produces chronic inflammation and increased permeability. This leads ruptures of the epithelial barrier, increased intracellular spaces, alteration of binding proteins and decreased activity of desmosomes, reversing these findings with the treatment. Alteration of these defense mechanisms may be the gateway for HSV infection.
On the other hand, HSV infection causes damage to the mucosa what favors contact with swallowed antigens and a Th2 response with eosinophilic infiltration.
The third hypothesis is related to the use of topical corticosteroids that has been associated with fungal infections, thanks to the local immunosuppression that they entail, increasing the risk of viral infections.
Although more studies are needed, it has been established that the lack of EoE treatment is an essential factor in the increased risk of HSV esophagitis. Therefore, adequate treatment of EoE to contain tissue inflammation is key to prevent this and other complications.

Clinical Case Summary

We describe the case of a 38-year-old patient referred to a general surgery consultation due to gastric polypoid lesions, suspected of neoplasia. Since the biopsies were negative for adenocarcinoma/dysplasia, another esophagogastroduodenoscopy was performed which showed several erythematous polypoid areas with a villous appearance, extensive and scattered, mainly in the gastric body and cardia. Only hyperplastic polyps were identified, without dysplasia. The patient underwent a colonoscopy which identified a pedunculated polyp with 50mm in the colon which was removed (serrated without dysplasia) and around 10 polyps measuring 5-10mm spread throughout the colon (two removed and identified as hyperplastic).
The mother underwent total gastrectomy for gastric polyposis associated with hypoalbuminemia and right hemicolectomy for cecum polyposis in 2004 (without access to the histology of the surgical specimens). During follow-up, colonoscopies were performed and the polyps removed were identified as hyperplastic.
The patient underwent a genetic study with a polyposis panel that detected a deletion of approximately 301.5kb that involved the entire SMAD4 gene, classified as pathogenic. Pathogenic variants in the SMAD4 gene are associated with Juvenile Polyposis syndrome (JPS), Myhre syndrome, and Juvenile Polyposis/Hereditary Hemorrhagic Telangiectasia. Given the clinical context, in the genetic consultation, it was assumed that it was Juvenile Polyposis syndrome, with autosomal dominant transmission. His mother will be tested for this mutation.

JPS is characterized by histologically characteristic hamartomatous polyps of the gastrointestinal tract, specifically in the stomach, small intestine, and colorectum. Patients with JPS associated with SMAD4 mutations are more likely to develop gastric polyps and have a higher risk of gastric cancer. To the authors' knowledge, this phenotype of hyperplastic/serrated polyps has not been described in patients with this pathology.

Clinical Case Summary

Introduction: Acute pancreatitis (AP) is an inflammatory condition of the pancreas that manifests with abdominal pain and elevation in serum pancreatic enzymes. Gastric retention following AP can occur due to gastric hypomotility or gastric outlet obstruction (GOO). GOO in AP is related to gastric outlet gastrointestinal edema or compression by necrotic/fluid collections.
Case Description/Methods: A 26-year-old female patient presented to our hospital with upper abdominal pain for 3 days. Her laboratory investigations showed elevated LFTs of a cholestatic pattern. Her MRCP revealed mild prominence of the CBD with distal tapering. She underwent ERCP with removal of a small CBD stone and CBD stent placement.
Afterward, the patient complained of constant epigastric and periumbilical pain associated with fever. Pancreatic enzymes were elevated, and CT abdomen was notable for prominent pancreas with peripancreatic stranding and fluid confirming the development of post-ERCP pancreatitis. She was managed with fluids and morphine for pain management. Ten days later, she reported left epigastric and upper abdominal pain that was different from the epigastric pain that followed the procedure. The pain was associated with nausea, recurrent vomiting and constipation. Repeated CT abdomen with contrast demonstrated noticeable extensive inflammatory changes within the region of the pancreatic head and newly developed significant gastric and proximal duodenal dilatation. Her clinical condition improved in the following days with conservative treatment with improvement in the abdominal pain and better tolerance to the oral diet.
Discussion: Our patient had early-onset GOO as a complication of AP, probably due to gastric outlet gastrointestinal edema, that resolved with conservative treatment. This is a complication that is easy to miss, especially in the early phase of the disease (< 4 weeks) when the patient’s pain and vomiting can be attributed to the AP itself.

Introduction

Long-term maintenance treatment efficacy, safety and tolerability in eosinophilic esophagitis (EoE) is still partially understood. The aim of this study was to evaluate long-term outcomes of maintenance treatment for EoE with various drugs and dose regimens in real-world observational studies and randomized controlled trials (RCTs).

Aims & Methods

Systematic search was performed on Pubmed-MEDLINE, Embase and Cochrane Central Register of Controlled Trials from inception to October 2023. Studies reporting histologic success of maintenance therapy for EoE patients > 48 weeks, following 8-12 weeks of induction therapy with the same drug were included. Primary outcome was pooled histologic success (defined as < 15 eosinophils/HPF) at the end of follow-up for both study designs. Risk Difference (RD) or Odds Ratio (ORs) for histological success of maintenance therapy versus placebo (PBO) (for RCTs) and versus induction (for both study designs), pooled drug-related adverse events (AEs), endoscopic and clinical success rates were assessed as secondary outcomes. Random effects model metanalyses were performed. A-priori sub-group analyses were performed to address substantial inter-study heterogeneity (measured with I² statistic).

Results

From 3,916 full articles, 23 articles matched inclusion criteria (17 observational studies and 6 RCTs), 7 with pediatric patients only. Overall, 1,923 patients (M 70.1%; mean age 29.8±12.6 years). Mean follow-up time was 78.4 weeks. Budesonide (either oro-dispersible or viscous suspension) was administered in 7 studies (including 2 RCTs), PPI in 6 studies (all observational, 4 pediatric), Fluticasone in 5 studies (including 1 RCT with 4 cohorts), Dupilumab in 2 RCTs and Cendakimab in 1 RTC. Pooled rate of long-term histologic success for RCTs was 83% (95% CI, 77%-89%; I² 73.1%), while for observational studies attested at 53% (95% CI, 42%-65%; I² 93.5%) at a median follow-up of 97.8 weeks. Maintenance therapy in RCTs showed a RD of -0.71 (95% CI; -0.92-0.50; p<0.01; I² 88.9%) versus PBO, while a RD of -0.06 (95% CI; -0.11-0.01; p<0.016; I² 23.1%) compared with induction. Observational studies showed a non-significant (p=0.38) Odds Ratio (OR) of 1.37 (95% CI, 0.66-2.85; I² 81.3%) of losing histologic success during therapy de-escalation. Pooled clinical success among RCTs attested at 61% (95% CI, 51%-75%; I² 71.3%), comparable with observational studies (60% [95% CI, 42%-77%; I² 97.3%]). Biological therapy (either Dupilumab or Cendakimab at various regimens) ranked first for pooled histologic success rate among RCTs with 79% (95% CI; 71%-87%; I² 54.9%). In observational studies, PPI with histologic success of 64% (95% CI, 50%-78%; I² 88.7%) and clinical success of 79% (95% CI; 66%-93%; I² 85.2%) ranked first. Pooled rate of AEs among RCTs attested at 34% (95% CI; 22%-45%; I² 93.2%), with a pooled candidiasis infection rate of 6% (95% CI; 2%-10%; I² 61.9%), comparable with pooled AEs among observational studies (5% [95% CI, 2%-7%; I² 66.7%]). Pooled therapy discontinuation rate was 0.14 (95% CI, 0.073-0.210, I² 94.49%) in real-world data.

Conclusion

This is the first meta-analysis on efficacy and safety of long-term maintenance treatment (median 78 weeks) for EoE. All treatments showed good efficacy in maintaining long-term histological remission without clear disadvantage in de-escalating therapy during maintenance in real-word data. Biological therapies resulted the most effective in RCTs, while PPIs in observational studies. Low adverse events rates and low therapy discontinuation rates confirm long-term treatment is well tolerated.

References

1. Nistel M, Andrews R, Furuta GT, Atkins D. Elimination Diet or Swallowed Topical Steroid Treatment of Pediatric Eosinophilic Esophagitis: Five-Year Outcomes. J Allergy Clin Immunol Pract. 2023 Aug;11(8):2516-2523.e2. doi: 10.1016/j.jaip.2023.05.036. Epub 2023 May 30. PMID: 37263351; PMCID: PMC10525024.

Disclosure

ES has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapa-gos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Uni-farco; has served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Takeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici.
Danese has served as a speaker, consultant and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Fer-ring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor.

Introduction

Esophagogastric junction contractile integral (EGJ-CI) is a metric of EGJ barrier function on high-resolution manometry (HRM), which may be limited by measurement discrepancies and unclear clinical utility. Mean EGJ basal pressure is a novel, simple HRM metric assessing barrier function. We compared their performance to predict conclusive gastroesophageal reflux disease (GERD).

Aims & Methods

Consecutive patients (Nov 2022-Oct 2023) undergoing combined HRM and 24 hour pH-impedance testing OFF antisecretory therapy (except for Barrett's patients) for known or suspected GERD were eligible, all with prior upper endoscopy. Mean (between end-expiration and end-inspiration) basal EGJ pressure, referenced to mean intragastric pressure, was calculated manually using the isobaric contour tool. EGJ-CI was calculated using the smart box tool, with the isobaric contour set 2 mmHg above intragastric pressure, over three respiratory cycles and normalized for its duration. On pH-impedance testing, Lyon classification 2.0 was applied. Conclusive GERD was defined as acid exposure time (AET) >6% or histologically confirmed Barrett’s. Mann-Whitney U and Kruskal-Wallis test, with Bonferroni correction, were used. ROC curves were plotted.

Results

125 patients were included (mean age 51.6 ± 16.5 years, 60% males). Upon applying Lyon 2.0 classification, 45 (36%) patients had conclusive GERD (25 Barrett’s), 7 (6%) borderline GERD, 16 (13%) reflux hypersensitivity (RH), while 57 (45%) had functional symptoms. Patients with conclusive GERD, on HRM, had a significantly lower mean basal EGJ pressure (11.0 vs 18.5 mmHg; p<0.001) than patients without conclusive GERD, while EGJ-CI was not statistically different (26.1 vs 35.1 mmHg∙cm; p=0.101). Mean basal EGJ pressure was significantly different across Lyon v2.0 subgroups (median values in GERD: 11, borderline GERD: 16, RH: 19, FH: 20 mmHg; p<0.001), while EGJ-CI did not differ (p=0.283). Mean basal EGJ pressure (AUROC: 0.73, 95%CI 0.64-0.82) showed greater predictive performance of conclusive GERD than EGJ-CI (AUROC: 0.59, 95%CI 0.49-0.69). The optimal cut-off of 13 mmHg had 72% sensitivity and 62% specificity; a cut-off of 9.5 mmHg had 86% sensitivity, while a cut-off of 23.5 mmHg had 91% specificity.

Conclusion

Mean EGJ basal pressure is a simple HRM metric to predict conclusive GERD, well differentiating GERD phenotypes, with greater performance than EGJ-CI. This metric could be preferred over EGJ-CI as a useful adjunctive measure to support GERD diagnosis.

Clinical Case Summary

A 69-year-old woman presented to the emergency department with a fever, diffuse abdominal pain rated 8/10 on the visual analog scale, and melena for two days. In the three months prior to admission, she had experienced pressure-like left-sided abdominal discomfort, early satiety, and gradual weight loss (9 kg). Her prior medical history was irrelevant. On physical examination, her vital signs were normal, but abdominal palpation was painful with tenderness. Laboratory tests revealed mild normocytic normochromic anemia (10.4 g/dL), leukocytosis (16x10^3/uL), and elevated C-reactive protein (13 mg/dL). A contrasted CT scan revealed supraclavicular, mediastinal, periportal, and perisplenic lymph nodes, with diameters up to 30 mm, splenomegaly, and a heterogenous 100 mm splenic mass that penetrated the gastric wall.
After multidisciplinary discussion, an esophagogastroscopy (EGD) was performed, which revealed a large non-bleeding ulcer on the greater curvature and anterior wall of the proximal corpus. Biopsies were taken, and the histology was compatible with high-grade large B-cell lymphoma with terminal lymphoplasmacytic differentiation. Fluorescence in situ hybridization revealed only BCL6 translocation. The diagnosis of primary splenic diffuse large B-cell lymphoma stage IV was made, and R-CHOP chemotherapy was initiated. After six cycles of chemotherapy, she had a partial response (persistent spleen disease), and radiotherapy was started. EGD was repeated, and no changes were detected apart from extensive scarring of the gastric mucosa.
Primary splenic diffuse large B-cell lymphoma (DLBCL) is a very rare type of non-Hodgkin's lymphoma (<1%), particularly in hepatitis C seronegative and immunocompetent patients. Abdominal pain is a key symptom of DLBCL; however, gastrointestinal bleeding is uncommon. In this case, EGD enabled the histological diagnosis, avoiding the need for more invasive methods and the untoward complications related to late treatment initiation.