Patients on Antithrombotic Agents with Small Bowel Bleeding -Yield of Small Bowel Capsule Endoscopy and Subsequent Management.

BACKGROUND AND AIMS: Small bowel gastrointestinal bleeding (GIB) is associated with multiple blood transfusions, prolonged and/or multiple hospital admissions, utilization of significant healthcare resources, and negative effects on patient quality of life. There is a well-recognized association between antithrombotic medications and small bowel GIB. We aimed to identify the diagnostic yield of small bowel capsule endoscopy (SBCE) in patients on antithrombotic medications and the impact of SBCE on treatment course. METHODS: The electronic medical records of nineteen hundred eighty-six patients undergoing SBCE were retrospectively reviewed. RESULTS: The diagnostic yield for detecting stigmata of recent bleeding and/or actively bleeding lesions in SBCE was higher in patients that were on antiplatelet agents (21.6%), patients on anticoagulation (22.5%), and in patients that had their SBCE performed while they were inpatient (21.8%), when compared to the patients not on antiplatelet agents (12.1%), patients not on anticoagulation (13.5%), and with patients that had their SBCE performed in the outpatient setting (12%). Of 318 patients who had stigmata of recent bleeding and/or actively bleeding lesion(s) identified on SBCE, SBCE findings prompted endoscopic evaluation (small bowel enteroscopy, esophagogastroduodenoscopy (EGD), and/or colonoscopy) in 25.2%, with endoscopic hemostasis attempted in 52.5%. CONCLUSIONS: Our study, the largest conducted to date, emphasizes the importance of performing SBCE as part of the evaluation for suspected small bowel bleeding, particularly in patients taking antithrombotic therapy, and especially during their inpatient hospital stay.

Endoscopic Treatment of Small Bowel Bleeding.

Approximately 5% of all gastrointestinal (GI) bleeding originates from the small bowel. Endoscopic therapy of small bowel bleeding should only be undertaken after consideration of the different options, and the risks, benefits, and alternatives of each option. Endoscopic therapy options for small bowel bleeding are like those treatments used for other forms of bleeding in the upper and lower GI tract. Available endoscopic treatment options include thermal therapy (eg, argon plasma coagulation and bipolar cautery), mechanical therapy (eg, hemoclips), and medical therapy (eg, diluted epinephrine injection). Patients with complicated comorbidities would benefit from evaluation and planning of available treatment options, including conservative and/or medical treatments, beyond endoscopic therapy.

Clinical Characteristics of Patients With Ineffective Esophageal Motility by Chicago Classification Version 4.0 Compared to Chicago Classification Version 3.0.

Background/Aims: Chicago classification version 4.0 (CCv4.0) of esophageal motility disorders developed a more stringent diagnostic criteria for ineffective esophageal motility (IEM) than version 3.0. We studied the implications of the new diagnostic criteria on the prevalence of IEM, and clinically characterized and compared the population of patients who no longer meet diagnostic criteria for IEM to those who retain the diagnosis. Methods: We included all consecutively performed high-resolution esophageal impedance manometries from 2014 to 2021. Three cohorts of patients with IEM were created: Patients with IEM by Chicago classification version 3.0 (CCv3.0; CC3 group), by CCv4.0 only (CC4 group), and by CCv3.0 who are now considered normal (Normal group). Demographics, manometric and reflux parameters, and clinical outcomes were compared. Results: A total of 594 manometries were analyzed. Of those, 66 (11.1%) met criteria for IEM by CCv3.0 (CC3), 41 (62.0%) retained an IEM diagnosis using CCv4.0 criteria (CC4), while 25 (38.0%) patients no longer met criteria for IEM (Normal). The CC4 group had higher esophageal acid exposure, especially supine (% time - 18.9% vs 2.2%; P = 0.005), less adequate peristaltic reserve (22.0% vs 88.0%; P = 0.003), and higher Demeester score (49.0 vs 21.2; P = 0.017) compared to the Normal group. There was no difference in bolus clearance between the groups. Conclusions: IEM under CCv4.0 has a stronger association with pathologic reflux, especially supine reflux, and inadequate peristaltic reserve, but impairment in bolus clearance is unchanged when compared with IEM diagnosed based on CCv3.0. Further studies are required to determine the implications of these findings on management strategies.

Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

OBJECTIVE: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. METHODS: In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. RESULTS: In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. CONCLUSION: RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

Increasing Prevalence and Racial Disparity of Alcohol-Related Gastrointestinal and Liver Disease During the COVID-19 Pandemic: A Population-Based National Study.

OBJECTIVES: One consequence of social distancing during the coronavirus disease 2019 (COVID-19) pandemic was an increase in alcohol use disorders. We postulated that this would be associated with a rise in alcohol-related gastrointestinal and liver disease. METHODS: Using Explorys Inc., an aggregate of electronic health records from US health care systems from 1999 to June 2021, we identified patients with "alcoholic hepatitis," "inflammation of pancreas caused by alcohol," and "alcoholic gastritis," based on Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). We compared patients utilizing health care during the pandemic to those before it. RESULTS: We identified 8,445,720 patients treated from June 21, 2020 to June 20, 2021 ("COVID cohort") and 65,587,860 patients treated before this ("pre-COVID cohort"). African American patients were more likely to be treated for all causes during COVID-19 [odds ratio (OR): 1.65; P <0.0001]. Alcoholic hepatitis (OR: 2.77), alcoholic pancreatitis (OR: 3.67), and alcoholic gastritis (OR: 1.70) (for each, P <0.0001) were more likely in all patients in the COVID cohort. African Americans in the COVID cohort were more likely to be diagnosed with alcoholic hepatitis (OR: 2.63), alcoholic pancreatitis (OR: 2.17), and alcoholic gastritis (OR: 3.09) [for each, P <0.0001]. CONCLUSIONS: The prevalence of alcohol-related liver and gastrointestinal disease increased during COVID-19. We suspect these increases are associated with increased alcohol use disorder resulting from the stress of social isolation. These data suggest COVID-19 disproportionately affected African Americans in overall health care utilization and increased burden of alcoholic gastrointestinal and liver disease.

Accuracy of Ultrasound Elastography and Fibrosis-4 Index (FIB-4) in Ruling Out Cirrhosis in Obese Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of advanced liver disease in the USA. Liver biopsy, the gold standard diagnostic test for evaluating liver fibrosis, is associated with significant risk and expense. The accuracy of ultrasound elastography and Fibrosis-4 index (FIB-4) in the obese NAFLD population is unknown. We aimed to compare the accuracy of ultrasound elastography and FIB-4 to liver biopsy in ruling out cirrhosis in NAFLD patients at a tertiary, transplant referral center in the US. METHODS: We retrospectively evaluated 93 patients with a mean age of 53 years (SD: 13 years) who underwent liver ultrasound elastography and liver biopsy, and additionally calculated their FIB-4 at the time of biopsy. We compared the liver stiffness measurement (LSM) obtained from ultrasound elastography and FIB-4 with the pathology results for ruling out cirrhosis. RESULTS: 85% of the patients were white, 53% were female, average BMI was 34.7 (SD: 6.7), 52% had diabetes, and 53% had hypertension. For biopsy-proven cirrhosis (prevalence 15%), a cut-off value of 12.5 kilopascals (kPa) for F4 had a sensitivity of 92% and a specificity of 54%. Values below this threshold excluded cirrhosis with 98% certainty. Compared to FIB-4, ultrasound elastography showed higher accuracy in ruling out cirrhosis (92% vs. 80% sensitivity, 98% vs. 95% negative predictive value (NPV), respectively). CONCLUSION: To our knowledge, this is the first study in a tertiary transplant referral center in the USA to show that ultrasound elastography was superior to FIB-4 and can be used as a reliable screening test to rule out cirrhosis in obese NAFLD patients at a 12.5 kPa cut-off. Therefore, helping to avoid the risk and expense associated with liver biopsy.

During HCV DAA Therapy Plasma Mip1B, IP10, and miRNA Profile Are Distinctly Associated with Subsequent Diagnosis of Hepatocellular Carcinoma: A Pilot Study.

Background: Hepatitis C virus (HCV) therapy lowers risk of hepatocellular carcinoma (HCC). Little is known about factors driving/preceding HCC in treated persons. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate host response and pathogenesis of disease. We investigated plasma levels of these RNAs and select serum markers before, during, and after HCV therapy, preceding HCC. Methods: Of 187 DAA treated HCV patients where therapy oriented longitudinal sampling was performed at a time without HCC diagnosis, 9 were subsequently diagnosed with HCC within 2 years of therapy. They were matched with 7 patients not diagnosed with HCC over the same time period. RNASeq was performed on plasma, and serum was assessed for biomarkers of inflammation by ELISA. Results: HCC diagnosis was 19 months (6-28) after therapy start in the HCC group. 73 and 63 miRs were differentially expressed at baseline (before DAA therapy) and 12 weeks after DAA therapy comparing HCC and non-HCC groups. Several lncRNA- showed differential expression as well. Several miRNA suppressors of cancer-related pathways, lncRNA- and mRNA-derived stabilized short RNAs were consistently absent in the plasma of patients who developed HCC. Serum IP10, and MCP-1 level was higher in the HCC group 12 weeks after therapy, and distinct miRNAs correlated with IP10 and MCP-1. Finally, in a focused analysis of 8 miRNAs best associated with HCC we observed expression of mi576 and mi-5189 correlation with expression of a select group of PBMC mRNA. Conclusions: These results are consistent with complex interplay between RNA-mediated host immune regulation and cancer suppression, strikingly skewed 12 weeks following therapy, prior to HCC diagnosis.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BACKGROUND: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here. METHODS: In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants. RESULTS: Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy. CONCLUSION: During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

T-cell Activation Is Correlated With Monocyte Activation in HCV/HIV Coinfection and Declines During HCV Direct-Acting Antiviral Therapy.

BACKGROUND: Immune activation markers associate with morbidity and mortality in HIV and hepatitis C virus (HCV) infection. We investigated how T-cell and monocyte activation are related over the course of HCV direct-acting antiviral (DAA) therapy during HCV/HIV coinfection. METHODS: Peripheral blood mononuclear cells from AIDS Clinical Trials Group (ACTG) A5329 participants and a single-site separate cohort treated with DAAs were analyzed for central memory (CM)/effector memory (EM) T-cell subsets, monocyte subsets, and cell activation (CD38 and HLA-DR expression) before, during, and after therapy. RESULTS: Before therapy, classical and inflammatory monocyte subset HLA-DR expression positively correlated with absolute counts and frequencies of CD38+HLA-DR+-expressing CD4+ and CD8 T cells and corresponding CM and EM subsets. After therapy initiation, CD38+HLA-DR+ co-expression on CD4+ and CD8+ memory T cells decreased by 12 weeks and 36 weeks, and plasma sCD14 positively correlated with CD38+HLA-DR+ CD4+ and CD4+CM T-cell frequencies. Monocyte subset activation remained similar over time. CONCLUSIONS: During HCV/HIV coinfection, memory T-cell activation is associated with monocyte subset activation, consistent with related underlying mechanisms. Following therapy initiation, memory T-cell, but not monocyte, activation decreased. Residual CD4+ T-cell activation after therapy completion is associated with sCD14, potentially linking the remaining CD4+ T-cell activation to residual factors driving activation in antiretroviral therapy-controlled HIV.

Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons.

Background: The mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown. Methods: We enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16). The cross-sectional cohort was stratified by cirrhosis state. Cell apoptosis/survival (AnnexinV+7AAD+/BCL-2 labeling) and cell cycle entry (Ki67 expression) of CD31+ and CD31- naïve CD4+ T cells was analyzed directly ex vivo and following 3 and 5 days of in vitro culture with media, interleukin (IL) -7 or CD3/CD28 activator. Results: In the cross-sectional cohort, naïve CD4+ proportions were lower in chronic HCV infected persons compared to controls and DAA-treated persons, an effect in part attributed to cirrhosis. Age was associated with naïve cell counts and proportions in HCV infected and treated persons as well. Naïve CD4+ cell proportions negatively correlated with plasma levels of soluble CD14 following therapy in DAA-treated persons. Naïve CD4+ cells from HCV infected persons exhibited greater direct ex vivo apoptosis and cell-cycling compared to cells from DAA-treated persons and controls, and this was localized to the CD4+CD31+ subset. On the other hand, no remarkable differences in expression of BCL-2 or IL-7 Receptor (CD127) at baseline or following in vitro media or IL7 containing culture were observed. In the longitudinal cohort, naïve CD4+CD31+/CD31- ratio tended to increase 24 weeks after DAA therapy initiation. Conclusions: Activation and apoptosis of peripheral naïve CD4+CD31+ T cells appear to contribute to naïve CD4+ lymphopenia in chronic HCV infection, and this defect is partially reversible with HCV DAA therapy. Age and cirrhosis -associated naïve CD4+ lymphopenia is present both before and after HCV DAA therapy. These findings have implications for restoration of host immune function after DAA therapy.

Adjuvant effect of type I interferon induced by many but not all commercial influenza vaccines.

BACKGROUND: Seasonal influenza vaccines approved and offered in the United States have varying reported degrees of effectiveness year over year and between manufacturers. Influenza vaccines produced from live virus may include single stranded RNA (ssRNA) that is a potent activator of the innate Toll-like receptor 7 (TLR-7) ligand. Plasmacytoid dendritic cells (pDC) can be activated by ssRNA to produce type I interferons such as IFN-α, which has been shown to have an adjuvant-like effect. OBJECTIVE: Our aim was to determine if IFN-α induction in peripheral blood mononuclear cells (PBMCs) exposed to eight different commercial influenza vaccines is a pDC-dependent process mediated through TLR-7 signaling. RESULTS: We demonstrate the ability of multiple vaccines to induce IFN-α in a TLR-7-dependent fashion. A number of vaccines however lacked IFN-α induction. The significance of these differences between vaccines is unclear, since all the approved vaccine formulations offer some degree of protection.

High Red Cell Distribution Width and Low Absolute Lymphocyte Count Associate With Subsequent Mortality in HCV Infection.

BACKGROUND: Hepatitis-C virus (HCV) chronic infection can lead to cirrhosis, hepatocellular carcinoma (HCC), end-stage liver disease, cardiovascular disease (CVD), and mortality. Transient Elastography (TE) is used to non-invasively assess fibrosis. Whether immune monitoring provides additive prognostic value is not established. Increased red-cell distribution width (RDW) and decreased absolute lymphocyte count (ALC) predict mortality in those without liver disease. Whether these relationships remain during HCV infection is unknown. MATERIALS AND METHODS: A retrospective cohort of 1,715 single-site VA Liver Clinic patients receiving Transient Elastography (TE) 2014-2019 to evaluate HCV-associated liver damage were evaluated for RDW and ALC in relation to traditional parameters of cardiovascular risk, liver health, development of HCC, and mortality. RESULTS: The cohort was 97% male, 55% African American, 26% with diabetes mellitus, 67% with hypertension, and 66% with tobacco use. After TE, 3% were subsequently diagnosed with HCC, and 12% (n=208) died. Most deaths (n=189) were due to non-liver causes. The TE score associated with prevalent CVD, positively correlated with atherosclerotic cardiovascular disease (ASCVD) 10-Year Risk Score, age, RDW, and negatively correlated with ALC. Patients with anisocytosis (RDW above 14%) or lymphopenia (ALC level under 1.2×109/L) had greater subsequent all-cause mortality, even after adjusting for age, TE score, and comorbidities. TE score, and to a modest degree RDW, were associated with subsequent liver-associated mortality, while TE score, RDW, and ALC were each independently associated with non-liver cause of death. CONCLUSION: Widely available mortality calculators generally require multiple pieces of clinical information. RDW and ALC, parameters collected on a single laboratory test that is commonly performed, prior to HCV therapy may be pragmatic markers of long-term risk of mortality.

Hepatitis C Virus (HCV) Direct-Acting Antiviral Therapy in Persons With Human Immunodeficiency Virus-HCV Genotype 1 Coinfection Resulting in High Rate of Sustained Virologic Response and Variable in Normalization of Soluble Markers of Immune Activation.

BACKGROUND: Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved. METHODS: We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks. RESULTS: Participants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point. CONCLUSIONS: During HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation. CLINICAL TRIALS REGISTRATION: NCT02194998.