Intraepithelial Eosinophils Research Articles

The Spectrum of Sarcina Colonization in the Gastrointestinal Tract of Pediatric and Adolescent Patients.

Introduction. Sarcina organisms are rare, gram-positive, sugar-fermenting cocci, identifiable in tissues only by histologic examination or molecular testing. Since its discovery, the pathogenicity and relevance of Sarcina in the human gastrointestinal tract has remained ill-defined. A recent literature review of 66 reported examples demonstrated the potential for severe complications such as emphysematous gastritis and gastric perforation. In pediatrics, colonization is associated with mucosal alterations and/or gastrointestinal dysmotility/obstruction with variable outcomes, including death secondary to gastric perforation. Yet, the features of Sarcina colonization within the gastrointestinal tract of adolescents are poorly understood and rarely reported. Methods. We present the gastrointestinal histopathological findings and the complete history of 4 pediatric patients with Sarcina colonization at our institution. Additionally a literature review with focus in the keywords "Sarcina" and "gastrointestinal' was performed, and the clinical and histopathological features of all previously reported examples of Sarcina in the gastrointestinal tract of pediatric patients were summarized. Results. All 4 patients had delayed gastric emptying, 3 of them due to neurologic disease, and one with pyloric obstruction due to duodenal ulceration with Helicobacter gastritis. In the 3 patients with available esophageal biopsies, it was associated to esophagitis with increased intraepithelial eosinophils. Conclusion. The potential pathogenicity of Sarcina colonization in the gastrointestinal tract of pediatric patients needs to be reevaluated. Due to potential serious complications, the identification of these organisms in the gastrointestinal tract sample should be reported and warrants further evaluation for possible gastrointestinal dysmotility or other mucosal alterations.

Esophageal epithelial Ikkβ deletion promotes eosinophilic esophagitis in experimental allergy mouse model.

Eosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood. To investigate the role of epithelial IKKβ/NFκB signaling in EoE pathogenesis using a mouse model with conditional Ikk β knockout in esophageal epithelial cells ( Ikk β EEC-KO ). EoE was induced in Ikkβ EEC-KO mice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes. Ikkβ EEC-KO /EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKβ/NFκB signaling pathways, with decreased expression of RELA and increased expression of IKKβ negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity. Our study demonstrates that loss of epithelial IKKβ signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkβ EEC-KO /EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE. Critical Role of Epithelial IKKβ/NFκB Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health.Molecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE. Relevance of the Ikkβ EEC-KO /EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies. This study reveals the crucial role of epithelial IKKβ/NFκB signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.

Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age

BackgroundDupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents.MethodsIn this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically.ResultsIn Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B.ConclusionsDupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.)

A213 DUPILUMAB EFFICACY IN EOSINOPHILIC ESOPHAGITIS PERSISTS FOR HISTOLOGIC, SYMPTOMATIC, AND ENDOSCOPIC OUTCOMES REGARDLESS OF CONCOMITANT HIGH-DOSE PROTON PUMP INHIBITOR USE

Abstract Background Proton-pump inhibitor (PPI) therapy is the most commonly used first-line therapy for eosinophilic esophagitis (EoE) but data informing long-term outcomes are limited. Aims This pre-specified analysis of data from the phase 3 LIBERTY EoE TREET (NCT03633617) study assessed the efficacy of weekly dupilumab vs placebo in patients (pts) with and without concomitant PPI use. Methods Pts with peak intraepithelial eosinophil (eos) count ≥15 eos/high-power field (hpf) after ≥8 weeks’ high-dose PPI were randomized to dupilumab or placebo. Pts on high-dose PPIs at screening remained on a high-dose regimen during the treatment period; switching of PPI types was permitted but new initiation of PPIs was prohibited. Endpoints at Week 24 were: proportion of pts achieving ≤6 eos/hpf, absolute change from baseline in Dysphagia Symptom Questionnaire (DSQ) score, % change in peak eos count, absolute change in Endoscopic Reference Score (EREFS) and Histologic Scoring System (HSS) grade/stage scores. Results In Parts A and B, respectively, 61.9% and 71.3% of pts in the dupilumab group and 64.1% and 72.2% in the placebo group were using PPIs at randomization. For pts treated with dupilumab vs placebo in Parts A and B, respectively, ≤6 eos/hpf was achieved by 69.2% (95% confidence interval [CI] 48.2–85.7) vs 8.0% (95% CI 1.0–26.0) and 59.6% (95% CI 45.8–72.4) vs 7.0% (95% CI 2.0–17.0) of pts using PPIs, and by 43.8% (95% CI 19.8–70.1) vs 0% (95% CI 0–23.2) and 56.5% (95% CI 34.5–76.8) vs 4.5% (95% CI 0.1–22.8) of pts not using PPIs. Least squares mean change from baseline in DSQ score for dupilumab vs placebo was –18.5 vs –12.9 and –21.8 vs –14.0 for pts using PPIs in Parts A and B, respectively, and –27.8 vs –3.8 and –28.4 vs –13.3 for those not using PPIs (Figure 1). Dupilumab improved outcomes vs placebo for secondary endpoints, with comparable results in pts with and without concomitant PPI use. Absolute change from baseline in EREFS score is shown in Figure 1. Dupilumab was generally well tolerated. Conclusions Dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE in adults and adolescents, up to 24 weeks, regardless of concomitant high-dose PPI use. Figure 1. Effect of dupilumab 300 mg qw versus placebo on primary endpoints (A) proportion of patients with peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (B) absolute change from baseline in DSQ total score at Week 24 (C) absolute change from baseline in EREFS total score at Week 24, by concomitant PPI use CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EREFS, endoscopic reference score; eos, eosinophils; hpf, high-power field; LS, least squares; PPI, proton pump inhibitor; pt, patient; qw, once weekly; SE, standard error. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

A204 DUPILUMAB IMPROVES HISTOLOGIC, ENDOSCOPIC, AND SYMPTOMATIC ASPECTS OF EOSINOPHILIC ESOPHAGITIS IN PATIENTS AGES 1–ampersand:003C12 YEARS

Abstract Background Dupilumab is approved in Canada for eosinophilic esophagitis (EoE) in patients (pts) aged ≥12 years who weigh ≥40 kg; no treatments are approved for pts aged ampersand:003C12 years. Aims The Phase 3 EoE KIDS trial evaluated dupilumab efficacy and safety vs placebo (PBO) in pts aged 1–ampersand:003C12 years with EoE. Methods Part A was a 16-week (W) PBO-controlled study; pts were randomized 2:2:1:1 to weight-tiered dupilumab on a higher-exposure (HE) or lower-exposure (LE) regimen, or PBO (2 groups) to W16. In Part B, pts continued dupilumab, or switched from PBO to dupilumab (HE/LE), to W52. Results At W16 (Part A), the HE dupilumab group had an improved proportion of pts achieving peak esophageal intraepithelial eosinophil count (PEC) ≤6 eosinophils/high-power field (hpf) vs PBO (67.6% vs 2.9%, Pampersand:003C0.0001; primary endpoint). At W52 (Part B), 62.9% of HE dupilumab/dupilumab pts, and 52.9% of PBO/HE dupilumab pts, achieved PEC ≤6. At W16, the following improved with HE dupilumab vs PBO: EoE-Histologic Scoring System grade and stage scores (–0.88 vs +0.02 and –0.84 vs +0.05, respectively, both Pampersand:003C0.0001); EoE-Endoscopic Reference Score (–3.5 vs +0.3, Pampersand:003C0.0001); overall caregiver assessed EoE status (global impression of change mean [SD], 2.1 [1.2] vs 3.3 [1.4]; lower scores represent more improvement). Improvements were maintained with continuous dupilumab and improved in PBO/dupilumab pts at W52. LE dupilumab maintained similar improvements achieved through W52; however, effects were generally either comparable or numerically lower with LE dupilumab vs HE dupilumab. At W16, COVID-19, rash, headache, and injection-site erythema occurred more frequently in patients receiving dupilumab, with higher incidence than PBO; AEs were similar through W52. Conclusions HE dupilumab met the primary endpoint of PEC ≤6 eos/hpf vs PBO, demonstrated significant changes in histologic and endoscopic aspects of EoE, and improved symptoms with benefits maintained/increased to W52. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Current smoking reduces small airway eosinophil counts in COPD.

Current smoking reduces small airway intraepithelial eosinophil counts in COPD patients and controls. This provides evidence of an attenuation of type-2 related inflammation in the small airways imposed by current smoking, which may affect ICS response. https://bit.ly/49YSKwG.

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

460. INTRAEPITHELIAL EOSINOPHILS IN ACHALASIA PATIENTS ARE NOT UNCOMMON, BUT THEY SEEM NOT RELATED TO THE COURSE OF THE DISEASE

Abstract Background The presence of intraepithelial eosinophils (IE) was described in patients with esophageal motor disorders (EMD). Conversely, EMD and even achalasia were reported in patients with eosinophilic esophagitis (EoE). The purpose of this study was to further investigate this possible association. Methods From February to July 2022, patients with achalasia undergoing laparoscopic myotomy were evaluated. Patients who had previous treatment were excluded. Immediately before the operation, the patients underwent endoscopy with the addition of 4 biopsies from the proximal, middle and distal esophagus and from the Z line, respectively. Two additional samplings of the esophageal muscle were taken while performing the myotomy. The specimens were stained with H&amp;E in order to highlight the presence of eosinophils and the number of IE eventually present in a high-power field (hpf) was recorded. Patients were re-evaluated 6 months after the operation. Results A total of 30 patients with a median age of 45.5 years were studied. Their preoperative ES was 6 (5–7) and the median duration of symptoms was 42 months (12–120); there were 18 stage I, 9 stage II, 2 stage III and only one stage IV, respectively; manometric subtype 1 was found in 7 patients, subtype 2 in 18 and subtype 3 in 5. There were no complications. All the patients had a good outcome and the median ES was 0 (0–1). IE were found in 6 patients (20%) [median 6/hpf (2–10)]. Only one patient met the pathologic criteria for EoE, whereas only one additional showed eosinophils in the muscular specimen. No differences in preoperative and postoperative data were found between patients with and without IE, but the maximum diameter of the gullet was narrower in the former than in the latter (3.24 cm vs 22.50 cm, respectively, p &amp;lt; 0.05). Conclusions EoE and achalasia are 2 of the commonest causes of dysphagia and an association between them was recently hypothesized. Our study confirmed that IE are present in some patients with achalasia, but seldom meeting the criteria for EoE. Only a narrower esophagus was found in patients with IE as compared to those without, possibly reflecting an earlier stage of the disease.

263. DUPILUMAB EFFICACY AND SAFETY TO 52 WEEKS IN ADULT AND ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS: RESULTS FROM LIBERTY EOE TREET

Abstract Background In Parts A and B of the 3-part, phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab 300 mg weekly (DPL qw) vs placebo (PBO) demonstrated significant efficacy and acceptable safety up to 24 weeks in adults and adolescents with eosinophilic esophagitis (EoE). Patients who completed Parts A and B entered Part C and received DPL qw to 52 weeks. Here we present 52-week results from patients who completed Part B and continued to Part C. Methods Of 80 DPL qw patients in Part B, 74 continued DPL qw in Part C (DPL/DPL). Of 79 PBO pts in Part B, 37 patients received DPL qw in Part C (PBO/DPL). Part B co-primary endpoints were proportion of patients achieving peak esophageal intraepithelial eosinophil (eos) count ≤6 eos/high- power field (hpf) and absolute change from Part B baseline in Dysphagia Symptom Score (DSQ) score at Week 24. Key secondary endpoints are listed in the Table. In Part C, all co-primary and secondary endpoints were assessed at Week 52 as secondary endpoints. Safety was also assessed. Results At Week 52, 84.6% of DPL/DPL and 67.6% of PBO/DPL patients achieved peak eos count ≤6 eos/hpf; mean (SD) absolute change from Part B baseline in DSQ score was −30.26 (15.39) for DPL/DPL and − 27.25 (11.46) for PBO/DPL patients. At Week 52, 100% of DPL/DPL and 78.4% of PBO/DPL patients achieved peak eos count &amp;lt;15 eos/hpf, 30.8% of DPL/DPL and 16.2% of PBO/DPL patients achieved peak eos count ≤1 eos/hpf, and compared to Part B baseline, peak eos count, EREFS, and HSS grade and stage scores were reduced (Table). DPL demonstrated an acceptable safety profile. Conclusion DPL qw demonstrated persistent improvements in clinical, symptomatic, histologic, and endoscopic features of EoE up to 52 weeks and had an acceptable safety profile. PBO patients from Part B who received DPL in Part C showed similar efficacy to dupilumab qw patients of Part B.

Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis

The current report describes a stepwise mechanistic pathway of NLRP3/caspase1/IL-18-regulated immune responses operational in eosinophilic esophagitis (EoE). We show that esophageal epithelial cells and macrophage-derived NLRP3 regulated IL-18 initiate the disease and induced IL-5 facilitates eosinophil growth and survival. We also found that A. fumigatus-exposed IL-18−/− mice or IL-18-neutralized mice are protected from EoE induction. Most importantly, we present that intravascular rIL-18 delivery to ΔdblGATA mice and CD2-IL-5 mice show the development of EoE characteristics feature like degranulated and intraepithelial eosinophils, basal cell hyperplasia, remodeling and fibrosis. Similarly, we show an induced NLRP3-caspase1-regulated IL-18 pathway is also operational in human EoE. Lastly, we present the evidence that inhibitors of NLRP3 and caspase-1 (MCC950, BHB, and VX-765) protect A. fumigatus- and corn-extract-induced EoE pathogenesis. In conclusion, the current study provides a new understanding by implicating NLRP3/caspase1-regulated IL-18 pathway in EoE pathogenesis. The study has the clinical significance and novel therapeutic strategy, which depletes only IL-18-responsive pathogenic eosinophils, not naïve IL-5-generated eosinophils critical for maintaining innate immunity.

Predictive Histologic Markers For Long-term Pediatric Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic esophageal type 2 inflammatory disease with ≥ 15 intraepithelial eosinophils per high power field (eos/HPF). There are no prognostic indicators for longitudinal disease response or disease progression. Persistent basal zone hyperplasia (BZH) following short-term therapy associates with endoscopic abnormalities and mast cell infiltration. We hypothesized that BZH might predict long-term EoE trajectory.

Beige Mucosa Reflecting Active Sites of Eosinophilic Esophagitis.

We evaluated a 30-year-old woman with a 7-year history of eosinophilic esophagitis (EoE) with an initial complaint of moderate dysphagia. She gradually recovered after receiving proton pump inhibitors and oral budesonide. Only proton pump inhibitors were continued as a maintenance therapy until she developed very mild dysphasia 2 months earlier. Although endoscopy using white light imaging revealed characteristic findings of EoE, such as furrows and rings, with unclear images (Figure A), narrow-band imaging (NBI) revealed beige mucosa regions more clearly (Figure B). Magnified endoscopy using NBI revealed dot-shaped intrapapillary capillary loops and the absence of subepithelial vessels in the beige mucosa (Figure C). Target biopsied beige mucosa specimens revealed numerous intraepithelial eosinophils with basal layer hyperplasia and dilated intercellular spaces, reflecting active sites of EoE, whereas in nonbeige mucosa, normal squamous epithelium with few eosinophils was observed (Figure D). A recent study revealed that the loss or thinning of the superficial differentiated cell layer due to EoE activity allows 415-nm light to contact the hemoglobin component, resulting in a beige color change under NBI (Ayaki M, et al. J Gastroenterol Hepatol. 2022). The presence of beige mucosa under NBI in EoE patients, especially in cases without prominent EoE characteristic findings in white light imaging, indicates a suitable biopsied site for correct EoE diagnosis along with its histological activity.

Laryngopharyngeal Lesion Appeared in a Patient With Eosinophilic Esophagitis

Question: A 52-year-old woman with eosinophilic esophagitis (EoE) stable on the potassium-competitive acid blocker vonoprazan (VPZ) was presented with a cobblestone-like lesion lying between the hypopharynx and the aryepiglottic fold (Figure A). The lesion was found on esophagogastroduodenoscopy (EGD) performed to examine her newly developed mild hemoptysis. The pharynx and larynx were intact 4 months earlier (Figure B). Chest radiography and sputum test for tuberculosis were negative. Her medical condition included dyslipidemia and urticaria. She did not drink alcohol or smoke cigarettes. For further assessment, she was referred to an otorhinolaryngologist, and subsequently the lesion was biopsied with the use of laryngoscopy under general anesthesia. Histologic evaluation found nuclear enlargement with spongiosis in the epithelium cells (Figure C) and remarkable infiltration of inflammatory cells in the subepithelial layer (Figure D). There was insignificant eosinophilia in the biopsies. p53 immunohistochemical staining showed a few positive epithelial cells (Figure E). In addition, enhanced computed tomography found no lymphadenopathy in the neck. On the basis of the findings, the lesion was diagnosed as possible low-grade dysplasia. From then on, she had been closely monitored, in which both the pharyngo-laryngeal lesion and EoE had not changed for 1 year until both conditions exacerbated with newly developed hoarseness. Esophageal biopsy showed increase in intraepithelial eosinophil counts up to 46 per high-power field (Figure F). For deterioration of EoE, topical corticosteroid (200 μg oral fluticasone twice per day) was added to VPZ. Her symptoms gradually improved, and 2 months later a follow-up EGD found significant improvement in not only EoE but also the pharyngo-laryngeal lesion (Figure G). This unexpected response to the treatment led to histologic reassessment of the lesion.

Beyond Neutrophils for Predicting Relapse and Remission in Ulcerative Colitis.

This study examines colonic histological features in ulcerative colitis [UC] in endoscopic remission to determine which cell types and biopsy sites best predict a patient's likelihood of remaining in remission. This is a retrospective chart, endoscopy and histology review of 166 patients with UC in endoscopic remission followed in a single inflammatory bowel disease practice over a median of 6 years [range, 2-11 years]. Clinical remission was based on global physician assessment and colonoscopy reports, and clinical relapse on chart review. Histological features of previous injury and also number and location of plasma cells and eosinophils were assessed. We evaluated all of these features semi-quantitatively using a standard set of illustrations for the grade to maintain consistency. Multiple logistic regression and survival analyses were used to identify features associated with relapse. Clinical relapse occurred in 44 patients. Ulceration, especially in the left colon, was highly predictive of relapse. In the absence of acute inflammation of ulceration, the variables most predictive of relapse were increased plasma cells in the basal 20% of the lamina propria, and eosinophils in the left colon. The variable most predictive of persistent remission was the presence of intra-epithelial eosinophils whether in the surface epithelium or within crypts, especially in the right colon. Lamina propria eosinophils [grade > 2] throughout the colon predicted relapse. In the absence of neutrophils or ulceration, left-sided plasmacytosis in the basal 20% of the lamina propria and increased lamina propria eosinophils provide the best indicators of relapse in UC in clinical and endoscopic remission.

S2180 Strongyloides-Associated Eosinophilic Colitis: Implications for Managing Renal Transplant Patients

Introduction: Strongyloides stercoralis is a parasitic intestinal nematode that is often asymptomatic but can cause life threatening hyperinfection syndrome (HIS) and disseminated disease (DD). Solid organ transplant patients require careful evaluation. Diagnostic challenges may allow patients to proceed to transplantation, increasing risk for HIS. These infections prove difficult to identify and treat, with high mortality rates. Case Description/Methods: A 57-year-old man with CKD on peritoneal dialysis and chronic pancreatitis complicated by pseudocyst formation with cyst gastrostomy undergoing renal transplant evaluation presented for chronic abdominal pain, daily diarrhea, postprandial dyspepsia and 35lb weight loss over 2 years. He required multiple hospitalizations and endoscopic evaluation without clear diagnosis. He was clinically stable on pancrelipase for presumed exocrine pancreatic insufficiency. Labs showed lipase 41, triglycerides 173, IgG4 32, WBC 9.6 with eosinophils 100/µL, Iron 79. Colonoscopy showed granular transverse colonic mucosa that was biopsied. Pathology showed intraepithelial and lamina propria eosinophils. Immunohistochemical staining for CD117 did not show increased mast cells. Follow up tryptase was 12.9 and eosinophils 660/µL. IgA 147, IgG 2253 and IgM 50. IgE was not assessed. Stool studies and allergy skin testing were negative. Strongyloides IgG antibody returned positive. He was treated with Ivermectin 15mg (200mcg/kg/day) induction for 2 days followed by Ivermectin 15mg for 2 days, 14 days later. Subsequent laboratory testing confirmed resolution with improvement in peripheral eosinophilia and with resolution of his diarrhea (Figure). Discussion: Strongyloides infection is well described in solid organ transplant patients. Larvae introduce enteric bacteria or fungi into the blood causing electrolyte disturbances, colonic ulceration, alveolar hemorrhage, severe sepsis and death. Morbidity and mortality, reaches 50% for HIS and 70% for DD. Diagnosis requires larvae identification but false negatives are high. Duodenal aspirates have better sensitivity at 76%. Serologic testing cannot distinguish between prior or active infection. A gelatin particle indirect agglutination test may be more reliable. First line treatment with Ivermectin induction with later treatment effectively eradicates organisms with cure rates between 94-100%. In our case, early detection may have prevented HIS and highlights the significance of early detection, particularly in pre-transplant patients.Figure 1.: Colonic eosinophilia (A) Increase in eosinophils within the mucosa and submucosa with preserved crypt architecture (H&E stain; 200X) (B) Intense focus of lamina propria eosinophilia accompanied by intraepithelial eosinophils (H&E stain; 400x) (C) Immunostaining for CD117 highlights rare mast cells (IHC stain; 200X).

S2372 Severe Dysphasia With Eosinophilic Esophagitis Pattern of Injury and Autoimmune Gastritis Related to Pembrolizumab Therapy

Introduction: Immune checkpoint inhibitor (ICI) therapies are effective treatments of many cancer types, including non-small cell lung carcinoma of the lung (NSCLC). While efficacious, ICI therapy can be associated with immune-related adverse effects (irAEs). We present a 67-year-old man with NSCLC who developed severe dysphasia with an eosinophilic esophagitis (EoE) pattern of injury on histopathology and concomitant autoimmune gastritis while on pembrolizumab maintenance therapy. Case Description/Methods: A 67-year-old man with NSCLC on 3 years of maintenance pembrolizumab with stable disease presented to GI clinic for evaluation of progressively worsening solid and liquid food dysphagia with regurgitation. Surveillance CT scans prior to advent of symptoms showed stable mediastinal lymphadenopathy with stable external compression of the mid-esophagus. A barium swallow study showed narrowing of the mid-esophagus. An EGD was performed and showed mid-esophageal lumen narrowing (Figure). Biopsies were obtained from the distal esophagus and showed up to 42 intraepithelial eosinophils (Eo) per high power field, consistent with an EoE pattern of injury. A subsequent EGD with stomach mapping prior to initiation of therapy showed concurrent autoimmune gastritis with no increase of Eo infiltrates. PPI therapy twice a day was initiated but the symptoms did not improve after 2 months. Topical glucocorticoid therapy with budesonide was then started. Despite dual therapy, his dysphagia progressed. Pembrolizumab was discontinued and docetaxel with ramucirumab was started, which resulted in a complete resolution of his dysphagia symptoms. Patient was maintained on PPI therapy with a plan to repeat EGD. Discussion: While GI irAEs are increasingly recognized, ICI-EoE is a rare entity. In the literature, only one other case of ICI-EoE has been reported. This patient’s dysphagia in the context of >15 intraepithelial Eo per high power field without other identifiable etiologies of increased esophageal Eo, and the resolution of symptoms with the discontinuation of pembrolizumab is consistent with ICI-EoE. In addition, the patient had concomitant autoimmune gastritis, which is also a rare but increasingly recognized irAE. Our case demonstrated both entities presenting in one patient. Treatment of irAEs often involves discontinuation of the ICI. Refractory cases may require systemic immunosuppression with corticosteroids or biologic therapy.Figure 1.: 1A – Mid-esophageal narrowing on barium swallow study Figure 1B – Intraepithelial eosinophilia consistent with EoE.

S2440 A Rare Cause of Dysphagia: Esophageal Stricture Due to Lichen Planus

Introduction: Esophageal lichen planus (ELP) is an unusual and under-recognized cause of dysphagia. Timely diagnosis is crucial for effective treatment as ELP has been associated with increased risk for development of squamous cell carcinoma. Case Description/Methods: A 72-year-old man presented with esophageal dysphagia to solids. Past medical history included oral lichen planus (LP) and osteoporosis with use of alendronate. He underwent endoscopy (EGD) which showed a proximal esophageal stricture for which balloon dilation ranging from 8 to 15 mm was done. Biopsy of the stricture showed esophageal mucosa with increased intraepithelial eosinophils (Figure). The working diagnosis was peptic stricture with possible eosinophilic esophagitis (EoE). He was started on pantoprazole 40 mg twice daily. He underwent 2 more EGDs with dilation for recurrent stricture and on the 2nd EGD, biopsy of the stricture showed numerous intraepithelial lymphocytes and focal apoptotic squamous cells (Civatte bodies) compatible with ELP. Budesonide slurry 1 mg twice daily was instituted and an EGD 6 months later showed near resolution of the stricture. The patient no longer requires dilations or antiacid therapy and is asymptomatic currently. He had Candida esophagitis 1 month after initiation of budesonide which was treated with fluconazole. Discussion: ELP is prevalent in patients with mucocutaneous forms of LP, most often oral LP. It is rarely seen in males with a case series by Franco et al describing the female to male ratio as 5:1. The endoscopic differential diagnosis for ELP should distinguish findings of esophagitis and stricture secondary to EoE, reflux esophagitis or esophageal Candidiasis. A low threshold should be kept for suspecting ELP in a patient with dysphagia and mucocutaneous LP. If histology is inconclusive but a high index of suspicion remains, particularly in patients with mucosal LP, repeating biopsies may be warranted for diagnosis as is highlighted in this case. A co-relation between longer duration of disease with severity of inflammation has been proposed with case series reporting strictures. Treatment includes serial dilations, topical and/or systemic steroids. Recurrence has been described despite topical steroid therapy with requirement of additional dilations. Successful use of immunomodulators such as cyclosporine, mycophenolate has been described. There is paucity of data regarding surveillance and optimal treatment for ELP, and thus further studies are needed for better understanding of this disease.Figure 1.: Esophageal biopsy showing esophageal squamous mucosa with basal cell hyperplasia, intraepithelial lymphocytes, and 2 apoptotic keratinocytes (Civatte or colloid bodies). Findings are compatible with esophageal lichen planus.

S2406 A Case of Cervical Esophageal Adenocarcinoma Arising From Gastric Inlet Patch: A Benign Lesion With Malignant Potential

Introduction: Esophageal adenocarcinoma is typically localized to the distal third of the esophagus. It is associated with long-standing acid reflux and resultant Barrett’s esophagus. In contrast, adenocarcinoma in the proximal esophagus without Barrett’s metaplasia is extremely rare. A gastric inlet patch (GIP) is a lesion of ectopic gastric mucosa usually found in the cervical esophagus and is considered a benign lesion. However, albeit rare, malignant transformation of GIP can occur. Here, we present a case of cervical esophageal adenocarcinoma arising from gastric inlet patch. Case Description/Methods: A 50-year-old male with GERD presented with a 6-month history of progressive dysphagia to solids and liquids and 20-pound weight loss. He reported a 1 pack-year smoking history but quit 30 years prior and consumed alcohol socially. Family history was negative for esophageal cancer. Upper endoscopy (HQ190F) showed a malignant stricture (2 cm long, 6mm diameter) at 18 cm from the incisors and a gastric inlet patch adjacent to the stricture. The endoscope was downsized (XP190N), and the stricture was dilated (24F) and traversed. The Z-line was at 40 cm with Barrett’s esophagus extending from 36 cm to 40 cm. Pathology of biopsies from the stricture showed acute and chronic inflammation with increased intraepithelial eosinophils suggestive of acid reflux. CT scan of the neck with contrast showed a heterogeneously enhancing ill-defined mass involving the cervical esophagus below the cricoid cartilage indenting the posterior margin of the trachea. Bronchoscopy was negative for bronchogenic cancer. Endoscopic ultrasound showed a non-circumferential hypoechoic mass in the cervical esophagus 18 cm from the incisors extending to 20 cm. The mass was predominantly extrinsic but was also noted to have a luminal component and poorly defined endosonographic borders. Pathology of FNAB showed moderately differentiated adenocarcinoma (Figure). Discussion: Proximal esophageal adenocarcinoma is extremely rare, making up less than 1% of esophageal cancers. Case studies have been published associating GIP and esophageal adenocarcinoma, but the pathogenesis of malignant transformation remains unclear. There are no established screening guidelines for ectopic gastric mucosa and routine biopsies are not recommended as dysplasia within GIP is rare. GIP may be overlooked during EGD and NBI exam may improve detection rates. Our case re-emphasizes careful examination of GIP and to strongly consider biopsy if abnormal.Figure 1.: A) Endoscopic view of malignant stricture 18 cm from incisors. Gastric inlet patch (arrow) adjacent to stricture. B) Endoscopic ultrasound image at the level of esophageal stricture showing irregular hypodensity suggestive of malignancy. C) Pathology of biopsy performed through fine needle aspiration (EUS) of upper esophageal mass demonstrating moderately differentiated adenocarcinoma, cribriform pattern, with mild nuclear pleomorphism, abundant mitoses, and apoptosis (H&E, 10x).

230. ENDOSCOPIC REFERENCE SCORE REMODELING SUBSCORE AND ESOPHAGEAL EOSINOPHIL COUNT DO NOT CORRELATE IN PLACEBO-TREATED EOSINOPHILIC ESOPHAGITIS PATIENTS FROM DUPILUMAB STUDIES

Abstract Although eosinophils are the hallmark of eosinophilic esophagitis (EoE) with threshold levels required for diagnosis, their exact role in EoE is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses endoscopic inflammatory (edema/exudate/furrows) and remodeling (rings/strictures) features. We assessed the correlations between peak esophageal intraepithelial eosinophil count (eos/high-power field [hpf]) and EREFS in placebo-treated EoE patients from two clinical trials: phase 2 proof-of-concept (POC; NCT02379052; n = 24) and part A of phase 3 TREET (Phase3-PartA; NCT03633617; n = 39). POC was a 12-week trial in adults and Phase3-PartA was a 24-week trial in adults and adolescents. Endoscopic examination of the esophagus was performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores and total score using EREFS (higher scores indicate greater severity). Peak eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between total/proximal/mid/distal eos/hpf and EREFS total, subscores, and components at BL, EOT, and for change from BL at EOT. Some strong correlations (r &amp;gt; 0.5) were observed between total peak eos/hpf and EREFS at BL in both studies and at EOT in Phase3-Part A (Table). Moderate-to-strong correlations (r &amp;gt; 0.3) were observed between total peak eos/hpf and EREFS inflammation subscore and edema/exudates/furrows individual components (some P &amp;gt; 0.5) in both studies. Correlations of total peak eos/hpf with EREFS remodeling subscore and rings/stricture components were not significant (P = 0.07–0.94). Peak eos/hpf in the proximal, mid, or distal esophagus were more strongly associated with EREFS inflammation subscore (majority moderate-to-strong correlations; P = 0.001–0.66) than EREFS remodeling subscore (weak correlations, P = 0.22–0.99) at BL/EOT for both studies. In these EoE patients, moderate-to-strong correlations were observed between eos/hpf and endoscopic markers of inflammation. No strong correlations were observed between total, proximal, mid, or distal peak eos/hpf and endoscopic parameters of remodeling. These data support a role for intact eosinophils in inflammatory changes in the esophagus in EoE and demonstrate the need for both histology and endoscopic evaluation. Further study, with larger sample sizes, is required to verify these findings in other contexts.

Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma.

Eosinophils are implicated as effector cells in asthma, but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation. In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation. Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type 2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that interleukin (IL)-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile. We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.