Background Coronavirus disease 2019 (COVID-19) is a growing pandemic that confers augmented risk for right ventricular (RV) dysfunction and dilation; the prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. Objectives The purpose of this study was to test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. Methods Consecutive COVID-19 inpatients undergoing clinical transthoracic echocardiography at 3 New York City hospitals were studied; images were analyzed by a central core laboratory blinded to clinical and biomarker data. Results In total, 510 patients (age 64 ± 14 years, 66% men) were studied; RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p = 0.007). During inpatient follow-up (median 20 days), 77% of patients had a study-related endpoint (death 32%, discharge 45%). RV dysfunction (hazard ratio [HR]: 2.57; 95% confidence interval [CI]: 1.49 to 4.43; p = 0.001) and dilation (HR: 1.43; 95% CI: 1.05 to 1.96; p = 0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR: 1.39; 95% CI: 1.01 to 1.90; p = 0.041). RV indices provided additional risk stratification beyond biomarker strata; risk for death was greatest among patients with adverse RV remodeling and positive biomarkers and was lesser among patients with isolated biomarker elevations (p ≤ 0.001). In multivariate analysis, adverse RV remodeling conferred a >2-fold increase in mortality risk, which remained significant (p < 0.01) when controlling for age and biomarker elevations; the predictive value of adverse RV remodeling was similar irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. Conclusions Adverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.
28Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of 29 coronavirus disease 2019 , is now pandemic with nearly three million cases 30 reported to date 1 . Although the majority of COVID-19 patients experience only mild or 31 moderate symptoms, a subset will progress to severe disease with pneumonia and acute 32 respiratory distress syndrome (ARDS) requiring mechanical ventilation 2 . Emerging results 33 indicate a dysregulated immune response characterized by runaway inflammation, 34including cytokine release syndrome (CRS), as the major driver of pathology in severe 35 -19 3,4 . With no treatments currently approved for COVID-19, therapeutics to 36 prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 37 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we 38 report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell 39 levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with 40 the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor 41 occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the 42 CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent 43 with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in 44 transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These 45 results demonstrate a novel approach to resolving unchecked inflammation, restoring 46 immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of 47 COVID MAIN TEXT 51 52Since the initial cases of COVID-19 were reported from Wuhan, China in December 53 2019 2 , SARS-CoV-2 has emerged as a global pandemic with an ever-increasing number 54 of severe cases requiring invasive external ventilation that threatens to overwhelm health 55
The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID‐19) in humans. Although most patients with COVID‐19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi‐organ failure, and death. RNA viruses such as SARS‐CoV‐2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS‐CoV‐2 infection pathology. Here, we examined genome‐wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally‐ill, critical COVID‐19 patients with confirmed SARS‐CoV‐2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID‐19 HIV coinfected individuals. Cell‐type deconvolution analyses confirmed lymphopenia in severe COVID‐19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID‐19 characterized by hypermethylation of IFN‐related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single‐cell transcriptional studies of severe COVID‐19. Epigenetic clock analyses revealed severe COVID‐19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID‐19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS‐CoV‐2.
Background and Aims The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication within enterocytes. Methods Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation and IBD treatment. Results A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and non-biologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. Additionally, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. Conclusions These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19.
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