Repressed Ang 1-7 in COVID-19 Is Inversely Associated with Inflammation and Coagulation.

The coronavirus SARS-CoV-2 infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which belongs to an anti-inflammatory, anti-thrombotic counter-regulatory arm of the renin-angiotensin system (RAS). ACE2 dysfunction and RAS dysregulation has been explored as a driving force in acute respiratory distress syndrome (ARDS), but data from COVID-19 patients has been inconsistent and inconclusive. We sought to identify disruptions of the classical (ACE)/angiotensin (Ang) II/Ang II type-1 receptor (AT1R) and the counter-regulatory ACE2/Ang 1-7/Mas Receptor (MasR) pathways in patients with COVID-19 and correlate these with severity of infection and markers of inflammation and coagulation. Ang II and Ang 1-7 levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) for 230 patients, 166 of whom were SARS-CoV-2+. Ang 1-7 was repressed in COVID-19 patients compared to that in SARS-CoV-2 negative outpatient controls. Since the control cohort was less sick than the SARS-CoV-2+ group, this association between decreased Ang 1-7 and COVID-19 cannot be attributed to COVID-19 specifically as opposed to critical illness more generally. Multivariable logistic regression analyses demonstrated that every 10-pg/mL increase in plasma Ang 1-7 was associated with a 3% reduction in the odds of hospitalization (adjusted odds ratio [AOR] 0.97, confidence interval [CI] 0.95 to 0.99) and a 3% reduction in odds of requiring oxygen supplementation (AOR 0.97, CI 0.95 to 0.99) and/or ventilation (AOR 0.97, CI 0.94 to 0.99). Ang 1-7 was also inversely associated with pro-inflammatory cytokines and d-dimer in this patient cohort, suggesting that reduced activity in this protective counter-regulatory arm of the RAS contributes to the hyper-immune response and diffuse coagulation activation documented in COVID-19. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a unique disease, COVID-19, which ranges in severity from asymptomatic to causing severe respiratory failure and death. Viral transmission throughout the world continues at a high rate despite the development and widespread use of effective vaccines. For those patients who contract COVID-19 and become severely ill, few therapeutic options have been shown to provide benefits and mortality rates are high. Additionally, the pathophysiology underlying COVID-19 disease presentation, progression, and severity is incompletely understood. The significance of our research is in confirming the role of renin-angiotensin system dysfunction in COVID-19 pathogenesis in a large cohort of patients with diverse disease severity and outcomes. Additionally, to our knowledge, this is the first study to pair angiotensin peptide levels with inflammatory and thrombotic markers. These data support the role of ongoing clinical trials examining renin-angiotensin system-targeted therapeutics for the treatment of COVID-19.

Identifying Communities at Risk for COVID-19-Related Burden Across 500 US Cities and Within New York City: Unsupervised Learning of the Coprevalence of Health Indicators.

BACKGROUND: Although it is well-known that older individuals with certain comorbidities are at the highest risk for complications related to COVID-19 including hospitalization and death, we lack tools to identify communities at the highest risk with fine-grained spatial resolution. Information collected at a county level obscures local risk and complex interactions between clinical comorbidities, the built environment, population factors, and other social determinants of health. OBJECTIVE: This study aims to develop a COVID-19 community risk score that summarizes complex disease prevalence together with age and sex, and compares the score to different social determinants of health indicators and built environment measures derived from satellite images using deep learning. METHODS: We developed a robust COVID-19 community risk score (COVID-19 risk score) that summarizes the complex disease co-occurrences (using data for 2019) for individual census tracts with unsupervised learning, selected on the basis of their association with risk for COVID-19 complications such as death. We mapped the COVID-19 risk score to corresponding zip codes in New York City and associated the score with COVID-19-related death. We further modeled the variance of the COVID-19 risk score using satellite imagery and social determinants of health. RESULTS: Using 2019 chronic disease data, the COVID-19 risk score described 85% of the variation in the co-occurrence of 15 diseases and health behaviors that are risk factors for COVID-19 complications among ~28,000 census tract neighborhoods (median population size of tracts 4091). The COVID-19 risk score was associated with a 40% greater risk for COVID-19-related death across New York City (April and September 2020) for a 1 SD change in the score (risk ratio for 1 SD change in COVID-19 risk score 1.4; P<.001) at the zip code level. Satellite imagery coupled with social determinants of health explain nearly 90% of the variance in the COVID-19 risk score in the United States in census tracts (r2=0.87). CONCLUSIONS: The COVID-19 risk score localizes risk at the census tract level and was able to predict COVID-19-related mortality in New York City. The built environment explained significant variations in the score, suggesting risk models could be enhanced with satellite imagery.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.