Necrotizing Esophagitis: A Big Squeeze?

Necrotizing esophagitis is rare and poorly understood. The etiologies reported in what little has been published (i.e., gastroesophageal reflux exacerbated by gastric outlet obstruction and low-flow ischemia) seem somewhat simplistic and lack any direct evidence. The following paper illustrates a recent clinical case while laying out arguments supporting esophageal spasm as a possible contributing factor.

Increasing Prevalence and Direct Health Care Cost of Inflammatory Bowel Disease Among Adults: A Population-Based Study From a Western Canadian Province

Objectives Our study aimed to calculate the prevalence and estimate the direct health care costs of inflammatory bowel disease (IBD), and test if trends in the prevalence and direct health care costs of IBD increased over two decades in the province of Saskatchewan, Canada. Methods We conducted a retrospective population-based cohort study using administrative health data of Saskatchewan between 1999/2000 and 2016/2017 fiscal years. A validated case definition was used to identify prevalent IBD cases. Direct health care costs were estimated in 2013/2014 Canadian dollars. Generalized linear models with generalized estimating equations tested the trend. Annual prevalence rates and direct health care costs were estimated along with their 95% confidence intervals (95%CI). Results In 2016/2017, 6468 IBD cases were observed in our cohort; Crohn’s disease: 3663 (56.6%), ulcerative colitis: 2805 (43.4%). The prevalence of IBD increased from 341/100,000 (95%CI 340 to 341) in 1999/2000 to 664/100,000 (95%CI 663 to 665) population in 2016/2017, resulting in a 3.3% (95%CI 2.4 to 4.3) average annual increase. The estimated average health care cost for each IBD patient increased from $1879 (95%CI 1686 to 2093) in 1999/2000 to $7185 (95%CI 6733 to 7668) in 2016/2017, corresponding to an average annual increase of 9.5% (95%CI 8.9 to 10.1). Conclusions Our results provide relevant information and analysis on the burden of IBD in Saskatchewan. The evidence of the constant increasing prevalence and health care cost trends of IBD needs to be recognized by health care decision-makers to promote cost-effective health care policies at provincial and national levels and respond to the needs of patients living with IBD.

A206 EVOLUTION OF PEDIATRIC AUTOIMMUNE CHOLANGITIS AND PRIMARY SCLEROSING CHOLANGITIS INTO ADULTHOOD

Background The natural history of primary sclerosing cholangitis (PSC) in children seems to differ from PSC in adults. However, studies on this matter have been limited by short follow-up periods and inconsistent classification of patients with autoimmune cholangitis (AIC) (or overlap syndrome). Consequently, it remains unclear if long-term outcomes are affected by the clinical phenotype. Aims The aims of this is study are to describe the long-term evolution of PSC and AIC in a pediatric cohort with extension of follow-up into adulthood and to evaluate the influence of phenotype on clinical outcomes. Methods This is a retrospective study of patients with AIC or PSC followed at CHU-Sainte-Justine, a pediatric referral center in Montreal. All charts between January 1998 and December 2019 were reviewed. Patients were classified as either AIC (duct disease on cholangiography with histological features of autoimmune hepatitis) or PSC (large or small duct disease on cholangiography and/or histology). Extension of follow-up after the age of 18 was done for patients followed at the Centre hospitalier de l’Université de Montréal. Clinical features at diagnosis, response to treatment at one year and liver-related outcomes were compared. Results 40 patients (27 PSC and 13 AIC) were followed for a median time of 71 months (range 2 to 347), with 52.5% followed into adulthood. 70% (28/40) had associated inflammatory bowel disease (IBD) (78% PSC vs 54% AIC; p=0.15). A similar proportion of patients had biopsy-proven significant fibrosis at diagnosis (45% PSC vs 67% AIC; p=0.23). Baseline liver tests were similar in both groups. At diagnosis, all patients were treated with ursodeoxycholic acid. Significantly more patients with AIC (77% AIC vs 30 % PSC; p=0.005) were initially treated with immunosuppressive drugs, without a significant difference in the use of Anti-TNF agents (0% AIC vs 15% PSC; p= 0.12). At one year, 55% (15/27) of patients in the PSC group had normal liver tests versus only 15% (2/13) in the AIC group (p=0.02). During follow-up, more liver-related events (cholangitis, liver transplant and cirrhosis) were reported in the AIC group (HR=3.7 (95% CI: 1.4–10), p=0.01). Abnormal liver tests at one year were a strong predictor of liver-related events during follow-up (HR=8.9(95% CI: 1.2–67.4), p=0.03), while having IBD was not (HR=0.48 (95% CI: 0.15–1.5), p=0.22). 5 patients required liver transplantation with no difference between both groups (8% CAI vs 15% CSP; p=0.53). Conclusions Pediatric patients with AIC and PSC show, at onset, similar stage of liver disease with comparable clinical and biochemical characteristics. However, patients with AIC receive more often immunosuppressive therapy and treatment response is less frequent. AIC is associated with more liver-related events and abnormal liver tests at one year are predictor of bad outcomes. Funding Agencies None

A38 TRPV1 VISCERAL AFFERENTS CONTROL CENTRAL SENSITIZATION IN IBD

Background Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease, suggesting a high level of plasticity in nociceptive circuits during acute phases. The establishment of chronic visceral pain results from neuroplasticity in nociceptors first, then along the entire neural axis, wherein microglia, the resident immune cells of the central nervous system, are critically involved. Our lab has shown that spinal microglia were key in controlling chronic pain state in IBD. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown. Aims To investigate the role of TRPV1+ visceral afferents in microglial activation and chronic visceral pain. Methods We generated DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice in which TRPV1 sensory neurons can be inhibited (TRPV1-hM4Di) or activated (TRPV1-hM3Dq) in a time and tissue specific manner using the inert ligand Clozapine-N-Oxide (CNO). To test the inhibition of TRPV1 neurons in DSS-induced colitis, TRPV1-hM4Di mice were treated with DSS 2.5% or water for 7 days and received vehicle or CNO i.p. injection twice daily. To activate TRPV1 visceral afferents, TRPV1-hM3Dq mice received vehicle or CNO daily for 7 days, by oral gavage. After 7 days of treatment, visceral pain was evaluated by colorectal distension and spinal cords tissues were harvested to measure microglial activation. Results Our data validated the nociceptor specific expression and function of the DREADD in TRPV1-Cre mice. Inhibition of TRPV1 visceral afferents in DSS TRPV1-hM4Di mice was able to prevent the colitis-induced microglial activation and thus reduce visceral hypersensitivity. In contrast, activation of TRPV1 visceral afferents in TRPV1-hM3Dq mice was sufficient to drive microglial activation in the absence of colitis. Analysis of the proalgesic mediators derived from activated TRPV1-hM3Dq neurons identified ATP as a key factor of microglial activation. Conclusions Overall, these data provide novel insights into the mechanistic understanding of the gut/brain axis in chronic visceral pain and suggest a role of purinergic signaling that could be harnessed for testing effective therapeutic approaches to relieve pain in IBD patients. Funding Agencies CCCACHRI (Alberta Children’s Hospital Research Institute) and CSM (Cumming School of Medicine) postdoctoral fellowship

A117 PROPOFOL SEDATION DOES NOT IMPROVE MEASURES OF COLONOSCOPY QUALITY – FINDINGS FROM THE SOUTHWEST ONTARIO COLONOSCOPY COHORT

Background The use of propofol during colonoscopy has gained increased popularity due to deeper anesthesia compared to conscious sedation. Prior studies examining the use of propofol sedation during colonoscopy have primarily focused on anesthesia outcomes. Whether propofol sedation is associated with improvements in colonoscopy outcomes is uncertain. Aims The primary outcome was adenoma detection rate (ADR). Secondary outcomes were the detection of any adenoma (conventional adenoma, sessile serrated polyp, and traditional serrated adenoma), sessile serrated polyp detection rate, polyp detection rate, cecal intubation rate, and perforation rate. Methods The Southwest Ontario Colonoscopy cohort consists of all patients who underwent colonoscopy between April 2017 and Oct 2018 at 21 hospitals serving a large geographic area in Southwest Ontario. Procedures performed in patients less than 18 years of age or by endoscopist who perform <50 colonoscopies/year were excluded. Data were collected through a mandatory quality assurance form that was completed by the endoscopist after each procedure. Pathology reports were manually reviewed. Results A total of 46,634 colonoscopies were performed by 75 physicians (37.5% by gastroenterologists, 60% by general surgeons, 2.5% others) of which 16,408 (35.2%) received propofol and 30,226 (64.8%) received conscious sedation (e.g. combination of a benzodiazepine and a narcotic). Patients who received propofol were likely to have a screening indication (49.2% vs 45.5%, p<0.0001), not have a trainee endoscopist present and be performed at a non-academic centre (32.2% vs 44.6%, p<0.0001). Compared to conscious sedation, use of propofol was associated with a lower ADR (24.6% vs. 27.0%, p<0.0001) and detection of any adenoma (27.7% vs. 29.8%, p<0.0001); no difference was observed in the detection ofsessile serrated polyps (5.0% vs. 4.7%, p=0.26), polyp detection rate (41.2% vs 41.2%, p=0.978), cecal intubation rate (97.1% vs. 96.8%, p=0.15) or perforation rate (0.04% vs. 0.06%,p=0.45). On multi-variable analysis, the use of propofol was not significantly associated with any improvement in ADR (RR=0.90, 95% CI 0.74–1.10, p=0.30), detection of any adenoma (RR=0.93, 95% CI 0.75–1.14, p=0.47), sessile serrated polyp detection rate (RR=1.20, 95%CI 0.90–1.60, p=0.22), polyp detection rate (RR=1.00, 95% CI 0.90–1.11, p=0.99), or cecal intubation rate (RR=1.00, 95%CI 0.80–1.26, p=0.99). Conclusions The use of propofol sedation does not improve colonoscopy quality metrics. Funding Agencies None

A75 IMPLEMENTING A CIRRHOSIS ORDER SET: A QUALITATIVE ANALYSIS OF PROVIDER-IDENTIFIED BARRIERS AND FACILITATORS

Background Cirrhosis is the leading cause of mortality and morbidity in individuals with gastrointestinal disease. Multiple care gaps exist for hospitalized patients with cirrhosis, resulting in high rates of re-hospitalization (e.g. 44% at 90 days in Alberta). The Cirrhosis Care Alberta (CCAB) is a 4-year multi-component pragmatic trial with an aim to reduce acute-care utilization by implementing an electronic order set and supporting education across eight hospital sites in Alberta. Aims As part of the pre-implementation evaluation, this qualitative study analyzed data from provider focus groups to identify barriers and facilitators to implementation. Methods We conducted focus groups at eight hospital sites with a total of 54 healthcare providers (3–12 per site). A semi-structured interview guide based upon constructs of the Consolidated Framework for Implementation Research (CFIR) and Normalization Process Theory (NPT) frameworks was used to guide the focus groups. Focus groups were recorded and transcribed verbatim. Data was analyzed thematically and inductively. Results Five major themes emerged across all eight sites: (i) understanding past implementation experiences, (ii) resource challenges, (iii) competing priorities among healthcare providers, (iv) system challenges, and (v) urban versus rural differences. Site-specific barriers included perceived lack of patient flow, time restraints, and concerns about the quality and quantity of past implementation interventions. Facilitators included passionate project champions, and an ample feedback process. Conclusions Focus groups were useful for identifying pre-implementation barriers and facilitators of an electronic orders set. Findings from this study are being refined to address the influence of COVID-19, and the data will be used to inform the intervention roll-out at each of the sites. Funding Agencies Alberta Innovates

A14 WIDE VARIATION IN CLINICAL MANAGEMENT OF PAEDIATRIC EOSINOPHILIC ESOPHAGITIS: A CANADIAN EXPERIENCE.

Background Eosinophilic esophagitis (EoE) is a chronic disorder treated by food elimination diet (FED), topical steroids and/or proton-pump inhibitors (PPI). Serial endoscopies and biopsies assess response to therapy. EoE management has evolved as guidelines are updated. Aims To identify practice variation among Canadian paediatric gastroenterologists (PG) who care for children with EoE. Methods An online survey using REDCap about decision-making in children with EoE was distributed to PG in Canada in November 2020. Results 62 PG completed the survey (response rate 69%, 62/94). The majority work in academic centres (92%). 3 centers indicated an accrual of >50 new patients per year; 9/16 centres have >100 patients in follow-up. An EoE Clinic is present in 5 centres. Diagnosis: Familiarity with the 2018 AGREE and 2020 AGA EoE guidelines was found to be 57% and 67% respectively. Criteria required to diagnose EoE according to current guidelines were correctly indicated by 42% of PG. (Figure 1). Endoscopy: The majority of PG (95%) adhere to guidelines in terms of required number and location of biopsies for the initial diagnosis. Ideal timing of repeat endoscopy after change in therapy in patients who are not in histological remission was 8–12 weeks by 67% of PG, timing in stable patients on maintenance therapy varied (33% only if patient is symptomatic). 25% used the EREFS Score in reporting endoscopic findings. Therapy: Improvement of symptoms was the highest ranked goal (64%), followed by remission of histologic findings (30%). A treatment algorithm was in place in 4 centers. The majority routinely assess adherence to therapy (73%) and consult a dietitian for FED (77%). Most (87%) do not consult an allergist for initial management. Preferred choices of 1st-line therapy varied among PG (Figure 2). When FED was selected, 32% of PG started with 1 food, 32% started with 2 foods, most frequently excluding dairy, followed by wheat. 14 (26%) start with ≥6 FED. Prescription of budesonide slurry was consistent among PG with doses of 1 and 2 mg/day in children <10 and >10 years, respectively. Conclusions The is the first Canadian study to assess the variation in management of children with EoE by PG. Overall, PG demonstrated good adherence to the guidelines in terms of initial diagnosis, but differences in maintenance therapy choice and timing of endoscopies. The results highlight a need for standardized management algorithms to deliver uniform care to this growing group. Grounding these guidelines in evidence will warrant a significant investment in further paediatric EoE research. Funding Agencies None

A50 MODULATION OF GOBLET CELL ACTIVITY DURING GIARDIA DUODENALIS INFECTION: A ROLE FOR PAR2

Background Giardia duodenalis has been shown to alter the structure of the intestinal mucus layers during infection via obscure mechanisms. We hypothesize that goblet cell activity may be disrupted in part due to proteolytic activation of protease-activated receptor 2 (PAR2) by Giardia proteases, resulting in disruption of mucus production and secretion by intestinal goblet cells. Aims Characterize alterations in goblet cell activity during Giardia infection, focusing on the roles of Giardia protease activity and PAR2. Methods Chinese hamster ovary cells transfected with nano-luciferase tagged PAR2 were incubated with Giardia NF or GSM trophozoites. Cleavage within the activation domain results in release of enzymes into the supernatant. Luminescence in the supernatant was measured as an indication of PAR cleavage by Giardia. LS174T, a human colonic mucus-producing cell line, was infected with Giardia trophozoites (isolates NF, WB, S2, and GSM). Prior to infection, trophozoites were treated with E64, a broad-spectrum cysteine protease inhibitor, and LS174T were treated with a PAR2 antagonist, a calcium chelator, or an ERK1/2 inhibitor. Quantitative PCR (qPCR) was performed for the MUC2 mucin gene. Wild-type (WT) and PAR2 knockout (KO) mice were infected with Giardia. Colonic mucus was stained using fluorescein-coupled wheat-germ agglutinin (WGA), and qPCR was performed for Muc2 and Muc5ac. Results Giardia trophozoites cleaved PAR2 within the N-terminal activation domain in a cysteine protease-dependent manner. Cleavage was isolate dependent, with isolates that show higher protease activity cleaving at a higher rate. High protease activity Giardia isolates increased MUC2 gene expression in LS714T. This increase was attenuated by inhibition of Giardia cysteine protease activity, and by antagonism of PAR2, inhibition of calcium release, or inhibition of ERK1/2 activity in LS174T cells. Both Muc2 and Muc5ac expression were upregulated in the colons of WT mice in response to Giardia infection, while in the jejunum Muc2 expression decreased and Muc5ac expression increased. In KO, no changes in gene expression were seen in the colon in response to Giardia infection, while in the jejunum, Muc2 expression was unchanged and Muc5ac expression decreased. Both WT infected and KO noninfected mice showed thinning of the colonic mucus layer compared to WT controls. There was some recovery in thickness in KO infected mice. Conclusions PAR2 plays a significant role in the regulation of mucin gene expression in mice and in a human colonic cell line. Results suggest that Giardia cysteine proteases cleave and activate PAR2, leading to calcium release and activation of the MAPK pathway in goblet cells, ultimately leading to altered mucin gene expression. Findings identify a novel regulatory pathway for mucus production by intestinal goblet cells. Funding Agencies CAG, CCC

A9 DORSAL ROOT GANGLIA NEURONAL RESPONSES AND SUBSTANCE P PRODUCTION ARE HIGHER IN MALE MICE

Background Abdominal pain is a common complaint in patients with chronic gastrointestinal disorders. Accumulating evidence suggests that gut microbiota is an important determinant of gut function, including visceral sensitivity. Germ-free (GF) mice have been shown to display visceral hypersensitivity, which normalizes after colonization. Sex also appears to play a key role in visceral sensitivity, as women report more abdominal pain than men. Thus, both gut bacteria and sex are important in the regulation of gut nociception, but the underlying mechanisms remain poorly understood. Aims To investigate the role of gut microbiota and sex in abdominal pain. Methods We used primary cultures of sensory neurons from dorsal root ganglia (DRG) of female and male conventionally raised (SPF) or germ-free (GF) mice (7–18 weeks old). To study the visceral afferent activity in vitro, calcium mobilization in DRG sensory neurons was measured by inverted fluorescence microscope using a fluorescent calcium probe Fluo-4 (1mM). Two parameters were considered i) the percentage of responding neurons ii) the intensity of the neuronal response. First, DRG sensory neurons were stimulated by a TRPV1 agonist capsaicin (12.5nM, 125nM and 1.25µM) or by a mixture of G-protein coupled receptors agonist (GPCR: bradykinin, histamine and serotonin; 1µM, 10µM and 100µM). We next measured the neuronal production of substance P and calcitonin gene-related peptide (CGRP), two neuropeptides associated with nociception, in response to capsaicin (1.25µM) or GPCR agonists (100µM) by ELISA and EIA, respectively. Results The percentage of neurons responding to capsaicin and GPCR agonists was similar in male and female SPF and GF mice. However, the intensity of the neuronal response was higher in SPF male compared to SPF female in response to capsaicin (125nM: p=0.0336; 1.25µM: p=0.033) but not to GPCR agonists. Neuronal activation was similar in GF and SPF mice of both sexes after administration of capsaicin or GPCR agonists. Furthermore, substance P and CGRP production by sensory neurons induced by capsaicin or GPCR agonists was similar in SPF and GF mice, regardless of sex. However, while the response to capsaicin was similar, the GPCR agonists-induced production of substance P was higher in SPF male mice compared to SPF females (p=0.003). The GPCR agonists-induced production of CGRP was similar in SPF male and female mice. Conclusions Our data suggest that at the level of DRG neurons, the absence of gut microbiota does not predispose to visceral hypersensitivity. The intensity of DRG neuronal responses to capsaicin and the GPCR agonists-induced production of substance P are higher in male compared to female mice, in contrast to previously published studies in various models of acute and chronic pain. Further studies are thus needed to investigate the role of sex in visceral sensitivity. Funding Agencies CIHR

A246 THE GLOBAL INCIDENCE OF ACUTE PANCREATITIS IS INCREASING OVER TIME: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background Acute pancreatitis is a common disease with significant associated morbidity and mortality. Historically, acute pancreatitis has been considered a disease with multiple etiologies and risk factors but is driven by alcohol and biliary disease. Multiple studies have shown that the incidence of acute pancreatitis is increasing globally among both adults and children. Aims The purpose of this study was to assess temporal trends in incidence of acute pancreatitis globally. Methods We performed a systematic literature search to identify population-based studies reporting the annual incidence of acute pancreatitis. Abstracts were independently assessed in duplicate to identify applicable papers for full-text review and data extraction. Joinpoint temporal trend analyses were performed to calculate the average annual percent change (AAPC) with 95% confidence intervals (CI). The AAPCs were pooled in a meta-analysis to capture the overall and regional trends in acute pancreatitis incidence over time. Temporal data were summarized in a static map and an interactive, web-based map to illustrate global differences. Results Forty-five studies reported the temporal incidence of acute pancreatitis (static map provided, online interactive map: https://kaplan-acute-pancreatitis-ucalgary.hub.arcgis.com/). The incidence of acute pancreatitis has increased from 1961 to 2016 (AAPC = 2.89%; 95% CI: 2.26, 3.52; n=41). Increasing incidence was observed in North America (AAPC = 2.71%; 95% CI: 1.93, 3.50; n=10) and Europe (AAPC = 2.79%; 95% CI: 1.95, 3.63; n=24). The incidence of acute pancreatitis was stable in Asia (AAPC = −0.28%; 95% CI: −5.03, 4.47; n=2). Conclusions This meta-analysis provides a comprehensive overview of the global incidence of acute pancreatitis over the last five decades and demonstrates a steadily rising incidence over time in most countries of the Western world. More studies are needed to better define the changing incidence of acute pancreatitis in Asia, Africa and Latin America. Funding Agencies None