Syndromic Antibiograms and Nursing Home Clinicians' Antibiotic Choices for Urinary Tract Infections.

Importance: Empirical antibiotic prescribing in nursing homes (NHs) is often suboptimal. The potential for antibiograms to improve empirical antibiotic decision-making in NHs remains poorly understood. Objective: To determine whether providing NH clinicians with a urinary antibiogram improves empirical antibiotic treatment of urinary tract infections (UTIs). Design, Setting, and Participants: This was a survey study using clinical vignettes. Participants were recruited via convenience sampling of professional organization listservs of NH clinicians practicing in the US from December 2021 through April 2022. Data were analyzed from July 2022 to June 2023. Interventions: Respondents were randomized to complete vignettes using a traditional antibiogram (TA), a weighted-incidence syndromic combination antibiogram (WISCA), or no tool. Participants randomized to antibiogram groups were asked to use the antibiogram to empirically prescribe an antibiotic. Participants randomized to the no tool group functioned as controls. Main Outcomes and Measures: Empirical antibiotic selections were characterized as microbiologically (1) active and (2) optimal according to route of administration and spectrum of activity. Results: Of 317 responses, 298 (95%) were included in the analysis. Duplicate responses (15 participants), location outside the US (2 participants), and uninterpretable responses (2 participants) were excluded. Most respondents were physicians (217 respondents [73%]) and had over 10 years of NH practice experience (155 respondents [52%]). A mixed-effects logistic model found that use of the TA (odds ratio [OR], 1.41; 95% CI, 1.19-1.68; P < .001) and WISCA (OR, 1.54; 95% CI, 1.30-1.84; P < .001) were statistically superior to no tool when choosing an active empirical antibiotic. A similarly constructed model found that use of the TA (OR, 1.94; 95% CI, 1.42-2.66; P < .001) and WISCA (OR, 1.7; 95% CI, 1.24-2.33; P = .003) were statistically superior to no tool when selecting an optimal empirical antibiotic. Although there were differences between tools within specific vignettes, when compared across all vignettes, the TA and WISCA performed similarly for active (OR, 1.09; 95% CI, 0.92-1.30; P = .59) and optimal (OR, 0.87; 95% CI, 0.64-1.20; P = .69) antibiotics. Conclusions and Relevance: Providing NH clinicians with a urinary antibiogram was associated with selection of active and optimal antibiotics when empirically treating UTIs under simulated conditions. Although the antibiogram format was not associated with decision-making in aggregate, context-specific effects may have been present, supporting further study of syndromic antibiograms in clinical practice.

Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.

Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.

Low rates of antibiotics prescribed during telehealth primary-care visits persisted during the coronavirus disease 2019 (COVID-19) pandemic.

For primary care clinics at a Veterans' Affairs (VA) medical center, the shift from in-person to telehealth visits during the coronavirus disease 2019 (COVID-19) pandemic was associated with low rates of antibiotic prescription. Understanding contextual factors associated with antibiotic prescription practices during telehealth visits may help promote antibiotic stewardship in primary care settings.

Neither Race nor Ethnicity Impact the Mortality of Residents of Veterans Affairs Community Living Center With COVID-19.

OBJECTIVES: COVID-19 disproportionately affected nursing home residents and people from racial and ethnic minorities in the United States. Nursing homes in the Veterans Affairs (VA) system, termed Community Living Centers (CLCs), belong to a national managed care system. In the period prior to the availability of vaccines, we examined whether residents from racial and ethnic minorities experienced disparities in COVID-19 related mortality. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Residents at 134 VA CLCs from April 14 to December 10, 2020. METHODS: We used the VA Corporate Data Warehouse to identify VA CLC residents with a positive SARS-CoV-2 polymerase chain reaction test during or 2 days prior to their admission and without a prior case of COVID-19. We assessed age, self-reported race/ethnicity, frailty, chronic medical conditions, Charlson comorbidity index, the annual quarter of the infection, and all-cause 30-day mortality. We estimated odds ratios and 95% confidence intervals of all-cause 30-day mortality using a mixed-effects multivariable logistic regression model. RESULTS: During the study period, 1133 CLC residents had an index positive SARS-CoV-2 test. Mortality at 30 days was 23% for White non-Hispanic residents, 15% for Black non-Hispanic residents, 10% for Hispanic residents, and 16% for other residents. Factors associated with increased 30-day mortality were age ≥70 years, Charlson comorbidity index ≥6, and a positive SARS-CoV-2 test between April 14 and June 30, 2020. Frailty, Black race, and Hispanic ethnicity were not independently associated with an increased risk of 30-day mortality. CONCLUSIONS AND IMPLICATIONS: Among a national cohort of VA CLC residents with COVID-19, neither Black race nor Hispanic ethnicity had a negative impact on survival. Further research is needed to determine factors within the VA health care system that mitigate the influence of systemic racism on COVID-19 outcomes in US nursing homes.

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.

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.

Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-ß Levels in Treated HIV+ Immune Non-responders.

Background: Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age. Methods: Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-ß and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts (n = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; n = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics. Results: Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-ß levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-ß negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets. Conclusions: INR have lower levels of TGF-ß and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.

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.

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.

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.

Achieving Sustained Viral Remission in Patients with Chronic HCV Infection and Cryoglobulinemic Vasculitis Does Not Always Correlate with Normalization of the Serologic Markers.

OBJECTIVE: We aim to describe the persistence of symptoms associated with HCV-associated cryoglobulinemic vasculitis following achievement of (SVR) with IFN- free direct acting antiviral (DAA) therapy. In particular, we describe the persistence of C4 hypocomplementemia and positive Rheumatoid Factor (RF). METHODS: We analyzed a case series of four patients enrolled from the Cleveland VA and known to have chronic HCV infection complicated by mixed cryoglobulinemia. The study included patients treated with interferon (IFN) based treatment and IFN free direct acting antiviral (DAA) therapy. RESULTS: Of the four patients, patients 1 and 2 experienced decline of RF without resolution following DAA therapy. Patient 1 continues to have evidence of disease following treatment. Patient 3 did not have resolution of RF during IFN-based treatment and experienced stabilization of kidney function while on treatment. Patient 4, previously a non-responder to IFN based treatment, experienced significant decline in RF titers along with resolution of cryoglobulin-associated rash with DAA therapy. C4 remained low following treatment in patients 1 and 3. Of the four patients, only patient 1 had prolonged persistence of cryoglobulinemia, measured at 3%, 17 months following achievement of SVR. CONCLUSIONS: We highlight the complexity of the viral-mediated immunologic mechanism that causes cryoglobulinemic vasculitis. Our cases also emphasize the need to consider cryoglobulinemic vasculitis as part of the differential diagnosis even with treated HCV infection. Recognizing these findings are important in our understanding of the pathophysiology of the disease and management in the era of IFN-free DAA therapy.