Mucosal Single-Cell Profiling of Crohn's-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets.

BACKGROUND & AIMS: The pathophysiology of Crohn's-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses. METHODS: Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry. RESULTS: The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells-inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments. CONCLUSIONS: CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.

Ileal Paneth Cell Phenotype is a Cellular Biomarker for Pouch Complications in Ulcerative Colitis.

BACKGROUND & AIMS: Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC. Because PC density is highest in the ileum, we further hypothesized that PCP predicts outcome in UC subjects who underwent total colectomy and ileal pouch-anal anastomosis (IPAA). METHODS: Uninflamed ileal resection margins from UC subjects with colectomy and IPAA were used for PCP and transcriptomic analyses. PCP was defined using defensin 5 immunofluorescence. Genotyping was performed using Immunochip. UC transcriptomic and genotype associations of PCP were incorporated with data from CD subjects to identify common IBD-related pathways and genes that regulate PCP. RESULTS: The prevalence of abnormal ileal PCP was 27%, comparable to that seen in CD. Combined analysis of UC and CD subjects showed that abnormal PCP was associated with transcriptomic pathways of secretory granule maturation and polymorphisms in innate immunity genes. Abnormal ileal PCP at the time of colectomy was also associated with pouch complications including de novo CD in the pouch and time to first episode of pouchitis. CONCLUSIONS: Ileal PCP is biologically and clinically relevant in UC and can be used as a biomarker in IBD.

Corticosteroids Increase the Risk of Invasive Fungal Infections More Than Tumor Necrosis Factor-Alpha Inhibitors in Patients With Inflammatory Bowel Disease.

Background: Invasive fungal infections are a devastating complication of inflammatory bowel disease (IBD) treatment. We aimed to determine the incidence of fungal infections in IBD patients and examine the risk with tumor necrosis factor-alpha inhibitors (anti-TNF) compared with corticosteroids. Methods: In a retrospective cohort study using the IBM MarketScan Commercial Database we identified US patients with IBD and at least 6 months enrollment from 2006 to 2018. The primary outcome was a composite of invasive fungal infections, identified by ICD-9/10-CM codes plus antifungal treatment. Tuberculosis (TB) infections were a secondary outcome, with infections presented as cases/100 000 person-years (PY). A proportional hazards model was used to determine the association of IBD medications (as time-dependent variables) and invasive fungal infections, controlling for comorbidities and IBD severity. Results: Among 652 920 patients with IBD, the rate of invasive fungal infections was 47.9 cases per 100 000 PY (95% CI 44.7-51.4), which was more than double the TB rate (22 cases [CI 20-24], per 100 000 PY). Histoplasmosis was the most common invasive fungal infection (12.0 cases [CI 10.4-13.8] per 100 000 PY). After controlling for comorbidities and IBD severity, corticosteroids (hazard ratio [HR] 5.4; CI 4.6-6.2) and anti-TNFs (HR 1.6; CI 1.3-2.1) were associated with invasive fungal infections. Conclusions: Invasive fungal infections are more common than TB in patients with IBD. The risk of invasive fungal infections with corticosteroids is more than double that of anti-TNFs. Minimizing corticosteroid use in IBD patients may decrease the risk of fungal infections.

Impact of COVID-19 on gastroenterology fellowship training: a multicenter analysis of endoscopy volumes.

Background and study aims The COVID-19 pandemic has had a profound impact on gastroenterology training programs. We aimed to objectively evaluate procedural training volume and impact of COVID-19 on gastroenterology fellowship programs in the United States. Methods This was a retrospective, multicenter study. Procedure volume data on upper and lower endoscopies performed by gastroenterology fellows was abstracted directly from the electronic medical record. The study period was stratified into 2 time periods: Study Period 1, SP1 (03/15/2020 to 06/30/2020) and Study Period 2, SP2 (07/01/2020 to 12/15/2020). Procedure volumes during SP1 and SP2 were compared to Historic Period 1 (HP1) (03/15/2019 to 06/30/2019) and Historic Period 2 (HP2) (07/01/2019 to 12/15/2019) as historical reference. Results Data from 23 gastroenterology fellowship programs (total procedures = 127,958) with a median of 284 fellows (range 273-289; representing 17.8 % of all trainees in the United States) were collected. Compared to HP1, fellows performed 53.6 % less procedures in SP1 (total volume: 28,808 vs 13,378; mean 105.52 ±â€Š71.94 vs 47.61 ±â€Š41.43 per fellow; P  < 0.0001). This reduction was significant across all three training years and for both lower and upper endoscopies ( P  < 0.0001). However, the reduction in volume was more pronounced for lower endoscopy compared to upper endoscopy [59.03 % (95 % CI: 58.2-59.86) vs 48.75 % (95 % CI: 47.96-49.54); P  < 0.0001]. The procedure volume in SP2 returned to near baseline of HP2 (total volume: 42,497 vs 43,275; mean 147.05 ±â€Š96.36 vs 150.78 ±â€Š99.67; P  = 0.65). Conclusions Although there was a significant reduction in fellows' endoscopy volume in the initial stages of the pandemic, adaptive mechanisms have resulted in a return of procedure volume to near baseline without ongoing impact on endoscopy training.

Outcomes of inflammatory bowel disease in patients with eosinophil-predominant colonic inflammation.

Background: Inflammatory bowel disease (IBD) is characterised by acute intestinal mucosal inflammation with chronic inflammatory features. Various degrees of mucosal eosinophilia are present along with the typical acute (neutrophil-predominant) inflammation. The effect of intestinal eosinophils on IBD outcomes remains unclear. Methods: This is a retrospective study. Archived intestinal mucosal biopsy specimens of treatment-naïve IBD patients were examined by two pathologists. The number of eosinophils per high-power field was counted, and the mucosal inflammation was classified according to the eosinophilic inflammatory patterns. Clinical outcomes during the follow-up period were recorded. Results: 142 treatment-naïve IBD patients were included. Mean age was 39 years. 83% of patients had ulcerative colitis, and median follow-up was 3 years. 41% of patients had disease flare(s) and 24% required hospitalisation. Eosinophil count was not associated with risk of disease flare or hospitalisation. Patients with neutrophil-predominant inflammation (>70% neutrophils) had greater risk of disease flare(s): 27(55%) versus 24(36%) and 7(28%) in patients with mixed and eosinophil-predominant inflammation, respectively (p=0.04). Overall, patients with neutrophil-predominant inflammation were more likely to have a disease flare; HR: 2.49, 95% CI (1.0 to 5.6). Hospitalisation rate was higher in patients with neutrophil-predominant inflammation: 17(35%) compared to 17(19%) in patients with eosinophil-rich inflammation (p=0.04). Kaplan-Meier analysis showed higher flare-free survival in patients with eosinophil-predominant inflammation compared to mixed and neutrophil-predominant inflammation. Conclusion: IBD patients with eosinophil-predominant inflammation phenotype might have reduced risk of disease flares and hospitalisation. Larger prospective studies to assess IBD outcomes in this subpopulation are warranted.

Efficacy of duodenal bulb biopsy for diagnosis of celiac disease: a systematic review and meta-analysis.

Background and study aims Although duodenal biopsy is considered the "gold standard" for diagnosis of celiac disease, the optimal location of biopsy within the small bowel for diagnosis remains unclear. The primary aim of this study was to perform a structured systematic review and meta-analysis to evaluate the diagnostic utility of endoscopic duodenal bulb biopsy for celiac disease. Patients and methods Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed from 2000 through December 2017. Review of titles/abstracts, full review of potentially relevant studies, and data abstraction was performed. Measured outcomes of adult and pediatric patients included location of biopsy, mean number of biopsies performed, and diagnosis of celiac disease as defined by the modified Marsh-Oberhuber classification. Results A total of 17 studies (n = 4050) were included. Seven studies evaluated adults and 11 studies assessed pediatric populations. Mean age of adults and pediatric patients was 46.70 ± 2.69 and 6.33 ± 1.26 years, respectively. Overall, sampling from the duodenal bulb demonstrated a 5 % (95 % CI 3 - 9; P  < 0.001) increase in the diagnostic yield of celiac disease. When stratified by pediatric and adult populations, duodenal bulb biopsy demonstrated a 4 % (95 % CI: 1 to 9; P  < 0.001) and 8 % (95 % CI: 6 to 10; P  < 0.001) increase in the diagnostic yield of celiac disease. Non-celiac histologic diagnoses including Brunner gland hyperplasia and peptic duodenitis were reported more commonly in the duodenal bulb as compared to the distal duodenum with an increase in diagnostic yield of 4 % (95 % CI 3 - 5; P  < 0.001) and 1 % (95 % CI 1 - 2; P  < 0.001), respectively. Conclusions Based upon our results, biopsy and histologic examination of duodenal bulb during routine upper endoscopy increases the diagnostic yield of celiac disease.

Anterior capsular rupture following blunt ocular injury.

A 10-year-old boy suffered a large, oblique anterior capsular tear following blunt injury to his right eye. The boy was followed daily for hyphema resolution and progressive traumatic cataract formation. After the hyphema had resolved, the lens was removed using an anterior approach and an intraocular lens was placed with excellent visual outcome.