Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials

Understanding mechanisms to promote successful aging in persons living with HIV

The mortality rate associated with HIV infection plummeted after the introduction of effective antiretroviral therapy pioneered two decades ago. As a result, HIV-infected people now have life expectancies comparable to that of HIV-uninfected individuals. Despite this, increased rates of osteoporosis, chronic liver disease, and in particular cardiovascular disease have been reported among people living with HIV infection. With the aging HIV-infected population, the burden of these comorbid illnesses may continue to accrue over time. In this paper, we present an overview of the aging HIV-infected population, its epidemiology and the many challenges faced. How to define and measure successful aging will also be reviewed. Finally, opportunities that may help mitigate the challenges identified and ensure successful aging among people living with HIV infection will be examined

Reduced endothelial dependent vasodilation in vessels from TLR4−/− mice is associated with increased superoxide generation

► The absence of TLR4 is associated with reduced endothelial cell function in mesenteric arteries. ► TLR4−/− mouse arteries have reduced acetylcholine responses. ► TLR4−/− have increased superoxide levels when stimulated with acetylcholine. ► An increase in superoxide generation reduces the activity of endothelial derived nitric oxide

Common antiretroviral combinations are associated with somatic depressive symptoms in women with HIV

Objective: While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. non-somatic symptoms. Design: Analysis of longitudinal data from the Women's Interagency HIV Study. Methods: Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment. Results: The analysis included 1,538 WWH who participated in 12,924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with non-somatic symptoms in any group. Conclusions: Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression

Plasma proteomics of SARS-CoV-2 infection and severity reveals impact on Alzheimer’s and coronary disease pathways

Summary: Identification of proteins dysregulated by COVID-19 infection is critically important for better understanding of its pathophysiology, building prognostic models, and identifying new targets. Plasma proteomic profiling of 4,301 proteins was performed in two independent datasets and tested for the association for three COVID-19 outcomes (infection, ventilation, and death). We identified 1,449 proteins consistently associated in both datasets with any of these three outcomes. We subsequently created highly accurate models that distinctively predict infection, ventilation, and death. These proteins were enriched in specific biological processes including cytokine signaling, Alzheimer’s disease, and coronary artery disease. Mendelian randomization and gene network analyses identified eight causal proteins and 141 highly connected hub proteins including 35 with known drug targets. Our findings provide distinctive prognostic biomarkers for two severe COVID-19 outcomes, reveal their relationship to Alzheimer’s disease and coronary artery disease, and identify potential therapeutic targets for COVID-19 outcomes

Subgroup analysis of differences in ordinal scale at days 28–35.

Estimated proportional odds ratios comparing day 28–35 ordinal scale in HCQ/CQ versus control groups. Estimates are given for the pooled patient population and for subgroups. Blue circles represent model-standardized estimates; blue horizontal lines represent 95% credible intervals. Open grey circles represent plug-in estimates; grey horizontal lines represent 95% confidence intervals. Grey circle size represents the number of patients in the corresponding subgroup. Arrows indicate uncertainty intervals extending beyond plot limits. Study acronyms are explained in Fig 1. Two trials did not have study acronyms (only trial registration numbers). Abbreviations: 95% CrI, 95% credible intervals; HCQ/CQ, hydroxychloroquine or chloroquine; NA, not applicable; NIV, noninvasive ventilation (includes BiPAP/CPAP and/or high-flow oxygen); OR, odds ratio.</p