Faculty Bibliography

OBJECTIVES:The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN:Prospective weekly hospital stress survey, November 2020-June 2022. SETTING:Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS:Thirteen hospitals across seven U.S. health systems. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% ( sd , 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS:During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.

UNLABELLED:Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES/OBJECTIVE:To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS/METHODS:Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES/METHODS:Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS:single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

IMPORTANCE: Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN, SETTING, AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log²increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10^-5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity.

Infectious disease outbreaks and pandemics have repeatedly threatened public health and have severely strained healthcare delivery systems throughout the past century. Pathogens causing respiratory illness, such as influenza viruses and coronaviruses, as well as the highly communicable viral hemorrhagic fevers, pose a large threat to the healthcare delivery system in the United States and worldwide. Through the Hospital Preparedness Program, within the US Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, a nationwide Regional Ebola Treatment Network (RETN) was developed, building upon a state- and jurisdiction-based tiered hospital approach. This network, spearheaded by the National Emerging Special Pathogens Training and Education Center, developed a conceptual framework and plan for the evolution of the RETN into the National Special Pathogen System of Care (NSPS). Building the NSPS strategy involved reviewing the literature and the initial framework used in forming the RETN and conducting an extensive stakeholder engagement process to identify gaps and develop solutions. From this, the NSPS strategy and implementation plan were formed. The resulting NSPS strategy is an ambitious but critical effort that will have impacts on the mitigation efforts of special pathogen threats for years to come.

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

INTRODUCTION: Hospitals experienced substantial stress during the COVID-19 pandemic-threats to standard operations- but it is not well known how this stress manifested at individual hospitals. We aimed to understand patterns of hospital stress over time, where stress was located within hospitals, and correlations between individual stress measures.
METHOD(S): We conducted a weekly hospital stress survey from November 2020 through May 2021 among site leaders from the SCCM Discovery Severe Acute Respiratory Infection - Preparedness (SARI-PREP) multicenter prospective cohort study. The survey assessed hospital stress ordinally and also assessed ED and ICU stress and deviations from standard operating procedures. Pairwise comparisons of strain measures were calculated by Pearson's correlation coefficients (r).
RESULT(S): Eight hospitals across three health systems in New York, California, and Washington contributed 190 hospital-weeks of data. Sites reported unavailability of some hospital resources resulting in potentially avoidable patient harm during 3.5% of hospital-weeks (with at least one such week at four hospitals); alterations in care processes and/or staffing which were fully compensated for during 57.9% of weeks; and no stress during 38.6% of weeks. During one December 2020 week, hospital stress, ICU stress, and care deviations were all present at 100% of reporting sites. The most common care deviations were increased hospital staffing (39.5%) and cancelling elective surgeries (18.6%). Hospital stress and care deviations were highly correlated (r = 0.81, p < 0.0001). Stress was more common in ICUs (72.4%) than EDs (14.3%), and ICU and ED stress were not correlated (r = 0.19, p = 0.05). While ED stress rose and abated earlier, ICU stress and care deviations persisted (range 2-13 weeks longer) as local case rates declined.
CONCLUSION(S): Hospital stress during the pandemic varied in degree and type both within and among hospitals over time. Care deviations were common but potentially avoidable patient harm was rare. Systematic national assessments of hospital stress, both during and between pandemics, could inform more rapid, proactive public health responses to novel threats. Areas for further study include impacts from persistent low-level stress and longer-term consequences for hospitals and their communities

OBJECTIVES: We designed a prospective cohort study to systematically study patients with severe acute respiratory infection (SARI) and improve hospital preparedness (SARI-PREP). The goal of this project is to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with SARI clinical outcomes and severity.
METHOD(S): In collaboration with the Society of Critical Care Medicine Discovery Research Network and the National Emerging Special Pathogen Training and Education Center (NETEC), SARIPREP is an ongoing, prospective, observational, multi-center cohort study of hospitalized patients with respiratory viral infections. We collected patient demographics, signs, symptoms, and medications; microbiology, imaging, and other diagnostics; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes. Hospital leadership completed a weekly hospital stress survey. Respiratory, blood, and urine biospecimens were collected from patients on days 0, 3, 7-14 after study enrollment and at hospital discharge. MEASUREMENTS AND MAIN RESULTS: SARI-PREP enrollment began on April 4, 2020 and currently includes 674 patients. Here we report results from the first 400 patients: 216 are from the University of Washington Hospitals, Seattle WA, 142 from New York University, New York NY and 42 from University of Southern California, Los Angeles, CA. Almost all tested positive for SARS-CoV-2 infection (n=397), whereas 3 patients tested positive for an alternative viral pathogen. The mean (+/-SD) age of the patients was 57+/-16 years; 72% were men, 62% were White, 14% were Asian, 12% were Black, and 31% were Hispanic. Most of the patients were admitted to the intensive care unit (96%). The median (interquartile range) hospital length of stay was 22 (9-46) days. Rates of invasive mechanical ventilation (72%) and renal replacement therapy (19%) were common and the rate of hospital mortality was 35%.
CONCLUSION(S): Initial SARI-PREP analysis indicates enrollment of a diverse population of hospitalized patients primarily with SARSCoV-2 infection. The demographics and clinical outcomes of our cohort mirror other large critically ill cohorts of COVID-19 patients. Results of a concomitant, weekly, hospital stress assessment are reported separately