ABSTRACT
Introduction: Coronavirus Disease 2019 (COVID-19) is an ongoing public health crisis that has sickened or precipitated death in millions. The etiologic agent of COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infects the intestinal epithelium and can persist long after the respiratory infection has cleared. We previously observed that intestinal SARS-CoV-2 infection levels varied by individual donors and did not correlate positively with ACE2, the cognate SARS-CoV-2 receptor. Therefore we aimed to delineate host factors that influence viral infection in the intestine. Methods: Published dataset GSE75214 was downloaded and expression levels of select genes were querried. Primary human ileal spheroids (enteroids), derived from healthy donors and patients with Crohn's disease (CD), were grown on 2D transwells until confluent. Cells were differentiated for 3d before infection with a modified vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-SARS-CoV-2) and GFP for 1h at a multiplicity of infection of ~0.5. Cells were harvested pre-infection and 24h after infection and expression of select genes was performed by qRT-PCR. Expression data were fit to a linear regression model to predict viral RNA levels. Results: Small intestine biopsy samples from CD patients demonstrated a reduction in ACE and an increase in CTSB and CTSL expression during active inflammation compared to healthy controls. Viral RNA expression did not correlate with ACE2 expression in CD enteroids. A subset of CD enteroids exhibited enhanced protease expression (TMPRSS2, TMPRSS4, CTSL), each of which correlated with higher viral RNA levels (P=0.04, P=0.002, P=0.006, respectively). Expression of these proteases was higher in the pre-infection for the sample subset. Principle component analysis of uninfected expression data demonstrated these samples clustered separately from the others, with the difference driven by TMPRSS2, TMPRSS4, and CTSL. Modeling viral RNA levels based on gene expression revealed expression levels of these proteases are a predictive expression signature. Conclusions: Host protease expression can predict SARS-CoV-2 infection and represent potential therapeutic targets for COVID-19. This is consistent with the recent report showing that cathepsin inhibition reduces SARS-CoV-2 spike-mediated syncytia formation. High expression of these proteases in the intestine may also be a novel biomarker for the risk of intestinal complications associated with COVID-19.(Figure Presented)RNA data from dataset GSE75214 demonstrating reduced ACE2 and increased CTSB and CTSL in patients with Crohn's disease during active inflammation compared to healthy controls. (Figure Presented) Enteroids from healthy control donors and patients with Crohn's disease were grown in 2D transwells and expression of indicated genes was assessed in pre-infection (A) and after infection with VSV-SARS-CoV-2 (B)
ABSTRACT
Background: Waning levels of anti-SARS-CoV-2 Spike (S) antibodies, particularly neutralizing, are associated with the risk of breakthrough infections. The impact of immunosuppression on antibody decay kinetics is unclear. We have previously reported a strong correlation between total anti-S antibodies and neutralization titers. Here, we report the decay kinetics in anti-S IgG antibodies across various immunosuppressive medications used in patients with CID. Methods: We recruited a volunteer sample of adults with confirmed CID eligible for SARS-CoV-2 vaccination in a prospective observational cohort study at two United States CID referral centers. All study participants received two doses of mRNA vaccine to SARSCoV- 2. To assess the durability of immunogenicity, anti-S IgG were measured at 7 (visit 3), 90 (visit 5), and 120 (visit 6) days after the 2nd dose of mRNA vaccine. The impact of various medications was assessed in repeated measures mixed model with the patient as a random effect, adjusting for gender and age, and using the group of patients on sulfasalazine, NSAIDs, or on no medications as a reference, using STATA. The half-life of anti-S IgG for a 50 percent reduction in titers at visit 3 was calculated for each medication class. Results: A total of 316 CID patients were recruited of which 148 (46.8%) had inflammatory bowel disease (IBD). Durability was assessed in 495 samples obtained in 293 patients. The arithmetic mean of anti-S IgG antibodies for each medication class at visits 3, 5, and 6 is shown in Figure 1. Overall, a 2-fold reduction in titers was observed from 7 to 90 days and 90 to 120 days (Table 1). The strongest decline was observed among patients on B cell depleting/ modulating therapies followed by those on combinations of biologics and/or small molecules and antimetabolites (methotrexate, leflunomide, thiopurines, mycophenolate mofetil, and teriflunomide). There was modest decline seen with TNFi (half-life 430.5 days, -2.15, 95% CI - 4.31 to - 1.07, p = 0.03). There was also a modest, but not significant, decline seen with Janus Kinase inhibitor (JAKi). No decline was seen with anti-IL-23 or anti-integrin medication classes. Conclusions: Antibody decay in patients with CID is not observed in patients on anti-integrins or anti-IL-23 while it is seen among patients on TNFi, JAKi, antimetabolites, and combinations of biologics and/or small molecules. Our data and those from other cohorts may be used to prioritize medication classes for boosting immunogenicity with additional doses of vaccination against SARS-CoV-2. Collection of antibody titers after booster doses is currently ongoing.(Table Presented) (Figure Presented) Figure 1: Durability of anti-spike IgG antibodies after vaccination against SARS-CoV-2 in patients with Chronic Inflammatory Disease
ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) has infected over 62 million people worldwide as of November 28, 2020. Emerging studies have revealed a high prevalence of gastrointestinal (GI) symptoms among patients with COVID-19, and coronavirus particles have been found in their stool. However, there are minimal data regarding the impact of COVID-19 severity on the GI system. In this study, we evaluated GI and hepatobiliary manifestations in a large number of hospitalized patients across the United States (US) with COVID-19 based on admission to the intensive care unit (ICU), a surrogate for COVID-19 severity. Methods: Seven US academic centers ed data from patients who had a positive COVID-19 test and were hospitalized. Demographics, presenting symptoms, clinical, and laboratory data were ed, as were hospitalization outcomes. Patients were stratified According to admission to the ICU (yes/no) during their hospital course. GI and hepatobiliary manifestations and outcomes were compared using the Chi-square test, and parametric laboratory values were compared using Student’s t test. Results: Of a total of 1,896 COVID-19 positive patients, 730 patients (38.5%) were admitted to the ICU (Table 1). ICU admissions were more likely to be male (64.2% vs. 52.1%;p<0.01). The most common presenting symptom was dyspnea in ICU patients (57.8%) versus cough in non-ICU patients (47.9%).The prevalence of patients reporting GI symptoms was similar between ICU and non-ICU patients (20.4% vs 21.1%;p=0.14). Compared with non-ICU patients, ICU patients had a higher prevalence of abnormal serum aspartate aminotransferase (AST) values (16.0% vs. 6.7%;p<0.01) and total bilirubin > 3 mg/dL (3.1% vs. 0.8%;p<0.01) (Table 2). There was not a significant difference in prevalence of abnormal alanine aminotransferase (ALT) values between the two groups (9.6% vs. 7.1%;p=0.13). The peak values of AST, ALT, and total bilirubin among all patients in the cohort were 3384 U/L, 1274 U/L, and 54 mg/dL, respectively. Conclusions: In a large US-based cohort of hospitalized patients with COVID-19, GI symptoms did not differ between ICU and non-ICU patients despite their high prevalence. ICU patients were more likely to have serum liver test abnormalities. In this context, further investigation is needed to clarify whether hepatobiliary dysfunction stems from direct injury from COVID-19 or an indirect effect of ICU-related multi-organ dysfunc-tion. Such insight would help guide future management to reduce the risk of and mitigate hepatic injury in these patients (Table Presented) (Table Presented)
ABSTRACT
Background: Coronavirus disease 2019 (COVID-19) has infected over 14 million people in the United States (US) as of December 1, 2020. Recent data have shown that COVID-19 strains appear to demonstrate geographic variation, such as Asian strains predominating in the Western US and European strains predominating in the Eastern US. However, the clinical significance of this variation remains unclear. In this large, multi-center cohort study, we evaluated gastrointestinal (GI) manifestations of COVID-19 regionally and throughout the US. Methods: Patients hospitalized with a positive COVID-19 test were identified at seven US academic centers. As a surrogate for differing COVID-19 strains, patients were stratified into regions (West, Midwest, or Northeast) depending on hospital location. Demographics, presenting symptoms, laboratory data, and hospitalization outcomes were ed. Statistical comparisons were performed with Chi-square and ANOVA tests, as appropriate. Results: A total of 1896 patients were identified (Table 1). Most patients were male (56.8%), and the most prevalent race was Caucasian (40.5%). The mean age was 58.1 years (±19.1), and the mean body mass index (BMI) was 29.9 (±8.4). A third (29.2%) of patients had a known COVID-19 exposure. The mean presenting temperature was 37.3 °C, and dyspnea was the most common presenting symptom (48.2%). GI symptoms were present in 20.3% of the overall cohort (Table 2);diarrhea was most common (12.4%), followed by nausea and/or vomiting (10.3%) and abdominal pain (6.0%). Geographically, GI symptoms were significantly less common in the Western cohort (17.8%) than the Northeastern (25.6%) and Midwestern (26.7%) cohorts. GI complications (GI hemorrhage and pancreatitis) were also significantly less common in the Western cohort (1.5%, 0.2%) than the Northeastern (6.9%, 1.5%) and Midwestern (3.3%, 1.7%) cohorts. The Midwestern cohort had a higher prevalence of moderately elevated serum aspartate aminotransferase (AST;23.5% vs 8.5% in Western and 10.5% in Northeastern cohorts;p<0.01). Compared to the Northeastern and Midwestern cohorts, the Western cohort had a higher prevalence of mildly elevated serum alanine aminotransferase (ALT;20.9% and 20.9% vs 28.5%;p=0.01) and total bilirubin (6.7% and 7.0% vs 11.4%;p=0.03). The presence of GI symptoms was not associated with increased mortality (p=0.15). Conclusions: Although GI manifestations were common among patients hospitalized with COVID-19, there is significant variability in prevalence across the US. GI symptoms and complications were less common in the West than the Northeast or Midwest. Our study highlights notable geographic variations in GI manifestations of COVID-19, prompting the need for further investigation into the mechanisms of these differences. Such insight could identify strategies that mitigate GI complications of COVID-19 infection.(Table presented) Demographic and Clinical Data of Patients with COVID-19 by Geographic Region. (Table presented) Gastrointestinal Manifestations of COVID-19 in Patients by Geographic Region.