Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial.

Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer-N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101-treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19.

SARS-CoV-2 Spike RBD-Induced Inflammatory Response by CD14+ Monocytes Causes Endothelial Barrier Dysfunction

Introduction Emerging research and clinical evidence suggest that severe COVID-19 is a microvascular disease, where SARS-CoV-2 infection triggers a rapid inflammatory vascular response that leads to endothelial dysfunction and thrombosis. Underlying medical conditions such as obesity, type 2 diabetes and hypertension, have been associated with increased risk for severe illness. SARS-CoV-2 enters cells by surface spike protein binding to host cell receptor angiotensin-converting enzyme 2 (ACE2). Isolated S protein of SARS-CoV-1 has been shown to induce an innate immune response. Here we investigate the cytokine response of monocytes with and without comorbidities (obesity and hypertension) exposed to SARS-CoV-2 spike protein, and the effects of this response on endothelial barrier function. Methods Human CD14+ monocytes (Lonza, Precision for Medicine) from two Caucasian males in their 50s, one with obesity and hypertension (HTN) and one without, were stimulated with LPS (100 ng/mL [positive control]), recombinant spike receptor-binding domain (RBD, 10 ug/mL) or serum-free media (negative control) for 48 hours. Monocyte conditioned media (MCM) was collected and cytokines (IL-6, IL-8, IL-10, IL-12p70, IL-1beta, IFN-gamma, TNF-alpha, IL-4) were analyzed by multiplex ELISA. Human lung microvascular endothelial cells (HLMVECs) from a healthy donor were exposed to MCM from healthy or HTN subjects. Endothelial barrier function was measured by electric cell-substrate impedance sensing (ECIS). Briefly, HLMVECs were seeded on ECIS chambers to proliferate until impedance plateaued. Half of the media was then replaced with MCM. Differences in impedance drops were compared among various conditions. Western blotting was used to investigate Spike RBD internalization. Results Spike RBD and resulted in increased IL-6, IL-8, IL-12p70, and TNF-alpha compared to negative control (Fig1A). Monocytes from HTN subject showed increased secretion of IL-6, IL-8 and IL-12p70 compared to those from the healthy subject (Fig 1B). HLMVECs showed moderate long-term barrier disruption, when treated with Spike RBD alone and Spike RBD with MCM from healthy subjects and no difference in transient barrier disruption or recovery. HLMVECs exposed to MCM from HTN subjects showed increased long-term barrier dysfunction, especially with Spike RBD present, and recovery of barrier function was also hampered (Fig 2). Spike RBD was observed to be internalized by both monocytes and HLMVECs. Discussion Spike RBD alone induces inflammatory cytokine secretion by CD14+ monocytes and is further increased in monocytes from the obese/HTN subject. Exposure to Spike RBD and MCM from both healthy and HTN subjects caused significant long-term endothelial barrier dysfunction in HLMVECs with increased dysfunction seen for the obese/HTN MCM. These results are consistent with clinical experience with the development of acute respiratory distress syndrome, increased disease severity, and worse outcome in COVID-19 patients with comorbidities. Further work is being done to characterize the cytokine profile and mechanisms of barrier dysfunction.

Severe Acute Respiratory Syndrome-Associated Coronavirus 2 Infection and Organ Dysfunction in the ICU: Opportunities for Translational Research.

OBJECTIVES: Since the beginning of the coronavirus disease 2019 pandemic, hundreds of thousands of patients have been treated in ICUs across the globe. The severe acute respiratory syndrome-associated coronavirus 2 virus enters cells via the angiotensin-converting enzyme 2 receptor and activates several distinct inflammatory pathways, resulting in hematologic abnormalities and dysfunction in respiratory, cardiac, gastrointestinal renal, endocrine, dermatologic, and neurologic systems. This review summarizes the current state of research in coronavirus disease 2019 pathophysiology within the context of potential organ-based disease mechanisms and opportunities for translational research. DATA SOURCES: Investigators from the Research Section of the Society of Critical Care Medicine were selected based on expertise in specific organ systems and research focus. Data were obtained from searches conducted in Medline via the PubMed portal, Directory of Open Access Journals, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, and Web of Science from an initial search from December 2019 to October 15, 2020, with a revised search to February 3, 2021. The medRxiv, Research Square, and clinical trial registries preprint servers also were searched to limit publication bias. STUDY SELECTION: Content experts selected studies that included mechanism-based relevance to the severe acute respiratory syndrome-associated coronavirus 2 virus or coronavirus disease 2019 disease. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Not applicable. CONCLUSIONS: Efforts to improve the care of critically ill coronavirus disease 2019 patients should be centered on understanding how severe acute respiratory syndrome-associated coronavirus 2 infection affects organ function. This review articulates specific targets for further research.