SIGNIFICANTLY REDUCED MORTALITY IN COVID-19 PATIENTS WITH GASTROINTESTINAL MANIFESTATIONS

Background: Gastrointestinal (GI) symptoms are the most common extrapulmonary manifestation of coronavirus disease 2019 (COVID-19). Therefore, we sought to determine the impact of GI symptoms on disease outcomes and the systemic inflammatory response in COVID-19. Methods: In two large, independent cohorts of hospitalized COVID-19 patients in the United States (n=634) and Italy (n=287) we examined GI symptoms on admission and related them to mortality and circulating proteomic biomarkers. Disease severity defined by oxygenation and end organ damage was also examined as an outcome in the US cohort. In both cohorts, a multivariate logistic regression was performed to determine the association of GI symptoms (nausea, vomiting, and diarrhea) present on admission and outcomes adjusting for age, gender and examined comorbid diseases. A prediction model was built based on the initial US cohort and validated with a distinct US cohort (n=242). In a subset of patients (n=238), circulating cytokines and chemokines were examined using a multiplexed proteomic assay (Olink) that simultaneously quantified 92 protein analytes. Results: A significant reduction in disease-associated mortality in COVID-19 patients presenting with GI symptoms was observed both in the US cohort (OR 0.54, 95% CI 0.34-0.86) and the Italian cohort (OR 0.33, 95% CI 0.13-0.67) which was independent of age, gender and comorbidities. A prediction model consisting of age and BMI with the addition of GI symptoms had a significantly improved ability to predict disease severity and mortality compared with age and BMI alone (median area under the curve (AUC) of 0.64 (age + BMI+ GI symptoms) vs 0.59 (age + BMI) for disease severity and 0.73 (age + BMI + GI symptoms) vs 0.70 (age + BMI) for mortality). The proteomic analysis revealed 6 clusters based on their co-segregation across all COVID-19 patients. Among these 6 clusters, clusters 4 and 5, which were enriched in the "Hallmark Inflammatory Response" and “KEGG JAK/STAT Signaling Pathway” respectively, and were reduced in patients with diarrhea. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with lower circulating levels of key inflammatory proteins including IL-6, IL-8, IL-17A and CCL28 that are known to be associated with poor outcomes in COVID-19;while there was an increase in IL-7 and TRAIL, which both have important immunoregulatory functions. Conclusions: COVID-19 patients with GI symptoms have reduced inflammatory biomarkers and improved survival after adjusting for comorbidities, age and gender. These data highlight GI involvement as an important parameter for severity stratification in COVID-19 and point towards an immunomodulatory role of the GI tract in response to SARS-CoV-2 infection. (Figure presented)

FIRST HIGH DIMENSIONAL EXAMINATION OF INTESTINAL BIOPSIES IN PATIENTS WITH COVID-19

Introduction: SARS-CoV-2, the causative pathogen for COVID-19, engages host ACE2 receptor for cellular entry. The brush border of the small intestines express high levels of ACE2. Gastrointestinal (GI) manifestations are common among COVID-19 patients. However, to date, there is limited information regarding intestinal response to SARS-CoV-2 infection. Methods: Intestinal biopsies were obtained from 17 COVID-19 patients (17.3 ± positive nasal swab) for cellular and transcriptomic analyses using mass cytometry and RNA-sequencing, respectively. Ten uninfected individuals served as compartment (EC) and lamina propria (LP) were analyzed separately. Results: The cellular profiles from LP of COVID-19 patients showed reduced frequencies of CD206+ conventional dendritic cells (CDC2s) and plasmacytoid (CD123+) dendritic cells Effector T cell (PD1+CD38+) frequency was increased in the LP and Intraepithelial lymphocytes (IEL) were increased in the EC of COVID-19 patients, with a concomitant decrease in CD206+ CDC2s. RNA sequencing active downregulation of genes involved in inflammatory pathways including IBD-associated pathways, while an upregulation of intestinal barrier function Gene expression of Neuropilin-1 (NRP-1), a putative SARS-CoV-2 receptor as well as key inflammatory cytokines (IL-1b, IFN-g, CCL24 and CXCL8) were significantly reduced in controls. A low intensity antiviral host response signature was observed predominantly in EC as opposed to LP suggesting viral localization to epithelium. Conclusions: Epithelial, myeloid and lymphoid cell alterations characterize intestinal response to SARS-CoV-2 infection with an unanticipated downregulation of key inflammatory pathways that have been implicated in adverse outcomes associated with These data stand in contrast to the inflammatory response reported in the systemic compartments and identify a potential mitigating role of the GI

CONVERSION RATE FOR COVID19 IN NEW YORK CITY: IMPACT OF SOCIAL DISTANCING AND UNIVERSAL MASKING

We reported the results of our multicenter cohort study in all patients who presented for endoscopy between March 1 and May 17 and were evaluated before their endoscopy for SARS-CoV2 and were followed after their endoscopy for COVID-19 status. This cohort enabled us to calculate the conversion rate from COVID-19 negative to positive during the study period and evaluate the change in conversion rate with the implementation of social distancing and masking at the population level in New York City. Data were retrieved from electronic medical records systems of six tertiary care centers in New York City. We identified all adult patients who had endoscopy between March 1, and May 17, 2020. Conversion was defined as having a negative COVID-19 status before endoscopy and a positive status afterwards. Participants COVID-19 status was defined based on SARS-CoV2 PCR test or a combination of symptoms (Fever plus at least one of: dyspnea, cough, dysgeusia, or anosmia). Patients were evaluated before endoscopy and then by phone or telehealth visit afterwards. Spline regression was used to evaluate the conversion rate before and after adoption of social distancing (March 20, 2020) and mandatory masks (April 15, 2020) in New York City. Of the 1467 patients presenting for endoscopy during the study period, we had follow-up data on 1222 patients (51% outpatient and 49% inpatient endoscopies). Overall, 78 participants (6.38 %) converted after endoscopy (74 with a positive PCR, and 4 with symptoms as defined above), at a median of 23 days after endoscopy (IQR 11 to 42 days). Patients had a mean age of 62±15 years, and were 62% male (n=48). Multivariable analysis demonstrated that date of endoscopy, institution, and presence of cardiovascular disease were the independent predictors of conversion after endoscopy, with cardiovascular disease associated with a more than 2 fold increase in the risk of conversion (OR=2.1, 95%CI 1.2-3.6, p=0.009). The range of conversion from the six institutions varied widely (1 to 11%, p=0.035). Overall, participants whose endoscopies were performed later during the study period had a lower risk of conversion (OR for one week=0.87, 95%CI 0.80-0.94, p=0.001). Before social distancing, conversion rate was 8.4% on average and was increasing by 2.3% per week (p<0.001). After social distancing, the conversion rate was 6.7% on average, and started to decrease by 4.2% per week (p<0.001). After mandatory masks, the conversion rate was 2.2% on average but has started to increase slowly by 0.9% per week (p<0.001;see figure 1). These findings do support decrease in conversion rate amongst New Yorkers who presented for endoscopy with the implementation of social distancing and mandatory masking. We believe the slow but significant increase in conversion rates by the end of May reflects the relative loosening in social distancing in New York City.(Figure Presented)

Women authorship in gastroenterology sustained during early COVID-19 pandemic

Introduction: Prior data indicate that within procedural specialties, women may be less likely to be first and senior authors of manuscripts during the COVID-19 pandemic, especially for studies pertaining to the pandemic. Women are more likely faced with challenges of balancing work and other duties such as household responsibilities and childcare, especially for those who are mothers. The purpose of this study was to determine the gender distribution of authorship of manuscripts in high-impact gastroenterology and hepatology journals during the early part of the COVID-19 pandemic. Methods: Manuscripts published between March 1, 2019 to January 1, 2020 and March 1, 2020 to January 1, 2021 in 16 high-impact gastroenterology and hepatology journals were identified using bibliometric data. Genders of first authors and senior authors were determined by matching first names with a predicted gender using a validated multinational database (Genderize.io). Number of women and men first and senior authors, and whether the manuscript was related to COVID-19 were recorded. Comparisons between female first and senior authorship of manuscripts from 2019 and 2020 were analyzed using Fisher exact testing. Results: In 2019, women were first authors of 777 (27.4%) manuscripts and senior authors of 546 (18.4%) manuscripts. In 2020, women were first authors of 999 (28.5%) manuscripts and senior authors of 646 (17.7%) manuscripts. There were no statistically significant differences of women first or senior authorship from 2019 to 2020. During the pandemic, women were first authors of 902 (28.9%) non-COVID-19 related manuscripts and 97 (25.7%) COVID-19 related manuscripts. Women were senior authors of 586 (18.0%) non-COVID-19 related manuscripts and 60 (15.6%) COVID-19 related manuscripts. There were no statistically significant differences of women authorship between non-COVID and COVID related manuscripts. Conclusion: The frequency and proportion of women first and senior authorship in 2020 was comparable to that in 2019. Women maintained scientific productivity in gastroenterology regarding publications in high-impact gastroenterology journals, despite facing increased challenges during the early part of the COVID-19 pandemic..

First high-dimensional examination of intestinal biopsies in patients with COVID-19

Background: SARS-CoV-2, the etiopathological agent for COVID-19, engages host ACE2 receptor for cellular entry. The brush border of the small intestines express high levels of ACE2 in physiological conditions. Gastrointestinal (GI) manifestations are common among COVID-19 patients. However, to date, there is limited information regarding intestinal response to SARS-CoV-2 infection. Methods: Intestinal biopsies were obtained from 17 COVID-19 patients (17.3-17.5 days from the last positive nasal swab) for cellular and transcriptomic analyses using mass cytometry and RNA-sequencing. Ten COVID-uninfected individuals served as controls. The epithelial compartment (EC) and lamina propria (LP) were analyzed separately. Results: The cellular profiles of intestinal tissues from COVID-19 patients showed reduced frequencies of CD206+ CDC2s and plasmacytoid dendritic cells in the LP of COVID-19 patients by mass cytometry. Effector T cell (PD1+CD38+) frequency was increased in the LP and blood of COVID-19 patients. Intraepithelial lymphocytes (IEL) were increased in the EC of COVID-19 patients, with a concomitant decrease in CD206+ CDC2s. RNA sequencing revealed an active downregulation of genes involved in inflammatory pathways including Th17 and IBD-associated pathways, while an upregulation of intestinal barrier function (mucin biosynthesis), amino acid metabolism and mineral absorption pathways was noted. Gene expression of Neuropilin-1 (NRP-1), a putative SARSCoV-2 receptor as well as key inflammatory cytokines (IL-1β, IFNγ, CCL24 and CXCL8) were significantly reduced in COVID-19 patients compared to controls. A low intensity antiviral host response signature was observed predominantly in EC reflecting the cellular localization of the virus. Conclusion: Epithelial, myeloid and lymphoid cell alterations characterize intestinal response to SARS-CoV-2 infection with an unanticipated downregulation of key inflammatory pathways that have been implicated in adverse outcomes associated with COVID-19. These data stand in contrast to reports from the pulmonary and systemic compartments and identify a potential mitigating role of the GI tract in COVID-19-associated immunopathology.