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.

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.

Background Immune activation markers associate with morbidity and mortality in HIV and 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 PBMC 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 out, plasma sCD14 positively correlated with CD38 +HLA-DR + CD4 + and CD4 +CM T-cell frequencies. Monocyte subset activation remained similar over time. Conclusion 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 remaining CD4 + T-cell activation to residual factors driving activation in ART controlled HIV.

Background/AimsChicago 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. MethodsWe 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. ResultsA 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. ConclusionsIEM 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.

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 1.2x109/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.

ObjectiveMorbidity 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 parameters relate to inflammation and mortality in RA were investigated.MethodsIn a retrospective single VA-Rheumatology Clinic cohort of 327 RA patients treated with methotrexate (MTX)+/-TNF-blocker 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.ResultsIn the local cohort, High RDW and Low ALC prior to MTX treatment each associated with subsequent mortality over 10 years (p<0.001 and p=0.004). The highest mortality was observed in those with both high-RDW and low ALC. This remained after adjusting for age and co-morbidities, and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in RA than controls, ALC correlated with plasma TNFR2, NK/Monocyte-HLADR-MFI, and CD4CM/CD8CMHLADR/CD38%, while RDW associated with CD4%/CD8% and CD4EM/CD4TE HLADR/CD38%. MTX initiation was followed by an increase in RDW and decrease in ALC. TNF-blocker therapy added to MTX resulted in an increase in ALC.ConclusionRDW and ALC before DMARD therapy associate with biomarkers of monocyte/macrophage inflammation and subsequent mortality. Mechanistic linkage between TNF signaling and lymphopenia here warrants further investigation.

BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionsActivation 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.

No abstract