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RATIONALE Immune dysregulation and endothelial injury are implicated in the pathobiology of acute respiratory distress syndrome (ARDS) due to COVID-19. Circulating biomarkers of immune and endothelial dysfunction are variably associated with outcomes in COVID-19 ARDS, with most studies conducted before routine use of systemic corticosteroids. We therefore evaluated the association of baseline inflammatory and endothelial biomarkers with mortality in a recent cohort of critically ill COVID-19 patients. METHODS We prospectively enrolled an observational cohort of COVID-19 ARDS patients from the intensive care unit (ICU) of an urban, academic hospital in Boston, Massachusetts from January 1 to March 1, 2021 (N=100). Patients were aged ≥ 18 years, had confirmed COVID-19 by polymerase chain reaction, and had a diagnosis of ARDS adjudicated by board-certified pulmonary and critical care physicians. Plasma samples were collected on day 1 of ICU admission. Clinical course was followed for 60 days post-enrollment or until discharge. Recorded clinical data included demographics, comorbidities, modified sequential organ failure assessment (mSOFA) score, hospital and ICU length of stay (LOS), and ventilator days. Eleven plasma analytes were measured using a Luminex Discovery Assay (R and D Systems) and Creactive protein (CRP) was measured by the hospital core laboratory. RESULTS Of 100 ICU patients with severe COVID-19 with acute respiratory failure, 74 were intubated and 68 had a plasma sample from day 1 of their ICU admission. Of those intubated (n=74), all met ARDS criteria, mean age (± standard deviation) was 64 ± 15 years, 39 (40%) were female, mean BMI was 30 ± 8, median mSOFA was 6 (IQR 4-8), median PaO2 was 105 mmHg (IQR 83-131 mmHg), and median PaO2/FiO2 was 174 (IQR 132- 235). Seventy patients (95%) received systemic corticosteroids. Median ventilator days was 15 (IQR 8-21), median ICU LOS was 17 days (IQR 10-27), and median hospital LOS was 22 days (IQR 16-32). At 30 days, 29 (40%) patients died, and at 60 days, 33 (45%) patients died. A total of 12 prespecified analytes were profiled (Figure). Only the endothelial biomarker von Willebrand factor (vWF) was associated with mortality at day 30 (∗P=0.003) and day 60 (P=0.002) using logistic regression adjusted for age, mSOFA, and multiple comparisons (P<0.004 significant by Bonferroni). CONCLUSION In a cohort of patients with ARDS due to COVID-19 receiving systemic corticosteroids, there was no association between inflammatory markers and mortality. However, the endothelial protein vWF remained associated with mortality suggesting endothelial injury is incompletely mitigated by systemic corticosteroids.
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Influenza and other respiratory viruses present a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as from COVID-19. A barrier to the development of effective therapeutics is the absence of a robust and predictive preclinical model, with most studies relying on a combination of in vitro screening with immortalized cell lines and low-throughput animal models. Here, we integrate human primary airway epithelial cells into a custom-engineered 96-device platform (PREDICT96-ALI) in which tissues are cultured in an array of microchannel-based culture chambers at an air-liquid interface, in a configuration compatible with high resolution in-situ imaging and real-time sensing. We apply this platform to influenza A virus and coronavirus infections, evaluating viral infection kinetics and antiviral agent dosing across multiple strains and donor populations of human primary cells. Human coronaviruses HCoV-NL63 and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for spike protein priming, and we confirm their expression, demonstrate infection across a range of multiplicities of infection, and evaluate the efficacy of camostat mesylate, a known inhibitor of HCoV-NL63 infection. This new capability can be used to address a major gap in the rapid assessment of therapeutic efficacy of small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.