Association of Intermediate-Stage Age-Related Macular Degeneration with Plasma Inflammatory Biomarkers in Persons with AIDS.

Purpose: To evaluate associations of plasma levels of inflammatory biomarkers with age-related macular degeneration (AMD) and cataract in persons with AIDS. Design: Nested case-control study (analysis 1) and nested cohort study (analysis 2). Participants: Analysis 1: persons with AIDS and incident intermediate-stage AMD (n = 26) and controls without AMD matched for age, race/ethnicity, and gender (n = 49) from The Longitudinal Study of Ocular Complications of AIDS. Analysis 2: 475 persons from LSOCA with baseline plasma biomarker levels followed prospectively for cataract. Methods: In both analyses, cryopreserved plasma specimens obtained at baseline were assayed for monocyte chemoattractant protein (MCP)-1 (CC motif chemokine ligand [CCL] 2), macrophage inflammatory protein (MIP)-1ß (CCL4), soluble tumor necrosis factor receptor (sTNFR) 2, interleukin (IL)-18, and fractalkine (CX3 motif chemokine ligand 1 [CX3CL1]). Main Outcome Measures: Analysis 1: mean difference (cases - controls) in plasma biomarker levels. Analysis 2: incident cataract. Results: After adjusting for plasma human immunodeficiency virus RNA level, CD4+ T-cell count, and smoking, elevated baseline plasma levels of sTNFR2 and IL-18 (mean differences [cases - controls] 0.11 log10[pg/mL]; 95% confidence interval [CI], 0.01-0.20; P = 0.024 and 0.13 log10[pg/mL]; 95% CI, 0.01-0.24; P = 0.037, respectively) each were associated with incident AMD. In a competing risk (with mortality) analysis, elevated baseline standardized log10 plasma levels of MCP-1, sTNFR2, IL-18, and fractalkine each were associated with a decreased cataract risk. Conclusions: When combined with previous data suggesting that AMD is associated with elevated plasma levels of C-reactive protein, soluble CD14, and possibly IL-6, the association of elevated plasma levels of sTNFR2 and IL-18 with incident AMD, but not with incident cataract, suggests that innate immune system activation, and possibly NLRP3 inflammasome activation, may play a role in the pathogenesis of AMD in this population. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Biological and Clinical Implications of the Vascular Endothelial Growth Factor Coreceptor Neuropilin-1 in Human Immunodeficiency Virus.

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.

Chronic viral coinfections differentially affect the likelihood of developing long COVID.

BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID.

The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. In a cohort of 280 adults with prior SARS-CoV-2 infection, we observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4 months following initial diagnosis were independently associated with serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia. Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52) and tended to have less severe (>5 symptoms reported) LC (OR 0.44). Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. SUMMARY: The authors found that Long COVID symptoms in a post-acute cohort were associated with serological evidence of recent EBV reactivation and pre-existing HIV infection when adjusted for participant factors, sample timing, comorbid conditions and prior hospitalization, whereas underlying CMV infection was associated with a decreased risk of Long COVID.

A multi-center study of fidaxomicin use for Clostridium difficile infection.

PURPOSE: Fidaxomicin use in real-world clinical practice, especially for severe Clostridium difficile infection (CDI), is mainly based on single-center observational studies. The purpose of this pharmacoepidemiology study was to assess outcomes of patients given fidaxomicin based on episode number and use of concomitant antibiotics. METHODS: Fidaxomicin use over time across included hospitals in the United States was assessed using a large inpatient drug utilization database. A multicenter retrospective chart review was also conducted of hospitalized patients with CDI that received fidaxomicin between 2011 and 2013. Fidaxomicin utilization and clinical outcomes were stratified by use of fidaxomicin for first or second episode (early episodes) versus greater than or equal to episodes (later episodes). RESULTS: The overall fidaxomicin use rate was 2.16 % which increased from 0.22 % in the last two quarters of 2011 to 3.16 % in the first two quarters of 2013. A total of 102 hospitalized patients that received fidaxomicin from 11 hospitals were identified in the multicenter study. Sixty-nine patients received fidaxomicin for early (68 % with severe CDI) and 33 received for later episodes. The majority of patients received other CDI therapy including 61 patients (88 %) for early episodes and 27 (82 %) for later episodes. Concomitant non-CDI antibiotics were received by 48 patients (47 %). Rates of clinical outcomes were similar regardless of CDI episode. CONCLUSION: This study demonstrated a slow but steady increase in fidaxomicin utilization over time; most of which was combined with other systemic antibiotics. Antimicrobial stewardship teams should provide guidance on appropriate use of fidaxomicin to optimize therapy and assess the need to continue other antibiotics during CDI treatment.

Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus.

OBJECTIVE: The premature atherosclerosis seen in patients with systemic lupus erythematosus (SLE) is not explained by traditional risk factors. SLE disease activity, such as renal involvement and presence of autoantibodies, is associated with elevated serum levels of type I interferon (IFN-I), a family of cytokines with potent antiviral and antiproliferative effects. This study was undertaken to test the hypothesis that elevated IFN-I levels could lead to endothelial dysfunction, a surrogate for cardiovascular disease, by causing a reduction in the number of endothelial progenitor cells (EPCs), bone marrow-derived cells that participate in endothelial repair. METHODS: EPCs were enumerated in the peripheral blood of SLE patients (n = 70) and healthy controls (n = 31), using a colony-forming assay. Serum IFN-I levels were quantified by real-time polymerase chain reaction measurement of the expression of the IFN-I-inducible gene MX1. Endothelial function was determined by peripheral arterial plethysmography. RESULTS: SLE patients had markedly reduced levels of EPC colony-forming units compared with controls (median 5.7/ml peripheral blood [interquartile range 1.9-12.8] versus 28.5/ml peripheral blood [14.7-47.3]; P < 0.0001), and the depletion of EPCs was more dramatic in patients with elevated levels of IFN-I. Stepwise multiple regression analysis showed that MX1 expression and serum levels of C-reactive protein were independently associated with the reduction of EPCs. Importantly, high IFN-I levels were associated with impaired endothelial function in patients with SLE. CONCLUSION: These data support the novel hypothesis that depletion of EPCs caused by excessive IFN-I may be linked to endothelial dysfunction and increased cardiovascular risk in SLE.