Challenges and Approaches to High-Level Isolation Unit Staffing and Just-in-Time Training: A Meeting Report.

In November 2022, the National Emerging Special Pathogens Training and Education Center hosted a virtual session with global high-level isolation unit (HLIU) representatives to discuss HLIU staffing challenges and approaches. Takeaways are relevant to healthcare institutions seeking solutions to recruit and retain their healthcare workforce amid unprecedented global staffing shortages.

Point-of-Care Lung Ultrasound Predicts Severe Disease and Death Due to COVID-19: A Prospective Cohort Study.

The clinical utility of point-of-care lung ultrasound (LUS) among hospitalized patients with COVID-19 is unclear. DESIGN: Prospective cohort study. SETTING: A large tertiary care center in Maryland, between April 2020 and September 2021. PATIENTS: Hospitalized adults (≥ 18 yr old) with positive severe acute respiratory syndrome coronavirus 2 reverse transcriptase-polymerase chain reaction results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28 days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean LUS Score (mLUSS) (ranging from 0 to 3) across lung zones was determined. The primary outcome was time to ICU-level care, defined as high-flow oxygen, noninvasive, or invasive mechanical ventilation, within 28 days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study; the median age was 61 years and 114 participants (43.2%) were female. The median mLUSS was 1.0 (interquartile range, 0.5-1.3). Following enrollment, 27 participants (10.0%) went on to require ICU-level care, and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (adjusted hazard ratio [aHR], 3.61; 95% CI, 1.27-10.2) and 28-day mortality (aHR, 3.10; 95% CI, 1.29-7.50). Pleural line abnormalities were independently associated with disease progression to death (aHR, 20.93; CI, 3.33-131.30). CONCLUSIONS: Participants with a mLUSS greater than or equal to 1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high-flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.

Developing a Rapid Response Single IRB Model for Conducting Research During a Public Health Emergency.

Research is foundational for evidence-based management of patients. Clinical research, however, takes time to plan, conduct, and disseminate-a luxury that is rarely available during a public health emergency. The University of Nebraska Medical Center (UNMC) developed a single institutional review board (IRB), with a vision to establish a rapid review resource for a network focused on clinical research of emerging pathogens in the United States. A core aspect of successful initiation of research during a pandemic or epidemic is the ability to operationalize an approach for rapid ethical review of human subject research and conduct those reviews at multiple sites-without losing any of the substantive aspects of ethics review. This process must be cultivated in anticipation of a public health emergency. US guidance for operationalizing IRB review for multisite research in a public health emergency is not well studied and processes are not well established. UNMC sought to address operational gaps and identify the unique procedural needs of rapid response single IRB (RR-sIRB) review of multisite research by conducting a series of preparedness exercises to develop and test the RR-sIRB model. For decades, emergency responder, healthcare, and public health organizations have conducted emergency preparedness exercises to test requirements for emergency response. In this article, we describe 2 types of simulation exercises conducted by UNMC: workshops and tabletops. This effort represents a unique use of emergency preparedness exercises to develop, refine, and test rapid review functions for an sIRB and to validate readiness of regulatory research processes. Such processes are crucial for conducting rapid, ethical, and sound clinical research in public health emergencies.

The Evolution of the National Special Pathogen System of Care.

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.

Opportunity Among Disaster: Reflecting on 2 Disaster Scenarios During the COVID-19 Pandemic.

Maintaining a public health emergency response for a sustained period of time requires availability of resources, physical and information technology infrastructure, and human capital. What perhaps is unprecedented is a medical center experiencing multiple disasters simultaneously. In this case study, the authors describe 2 separate disaster events experienced during the ongoing COVID-19 pandemic: (1) a cyberattack at Nebraska Medicine in Omaha, Nebraska, and (2) civil unrest following the murder of George Floyd in Minneapolis, Minnesota. Although these settings were very different, the following common themes can inform future disaster planning: the benefit of an already active incident command system, the prescient need for continuity of operations, and the anticipation of workforce fatigue. These dual-disaster experiences provide an opportunity to identify lessons learned that will drive improvements in emergency management through preparedness and mitigation measures and response innovations for future simultaneous disasters.

Contributions of the Regional Emerging Special Pathogen Treatment Centers to the US COVID-19 Pandemic Response.

The National Emerging Special Pathogens Training and Education Center (NETEC) was established in 2015 to improve the capabilities of healthcare facilities to provide safe and effective care to patients with Ebola and other special pathogens in the United States. Through NETEC, a collaborative network of 10 Regional Emerging Special Pathogen Treatment Centers (RESPTCs) undertook readiness activities that included potential respiratory pathogens. These preparations, which took place before the COVID-19 pandemic, established a foundation of readiness that enabled RESPTCs to play a pivotal role in the US COVID-19 pandemic response. As initial COVID-19 cases were detected in the United States, RESPTCs provided essential isolation capacity, supplies, and subject matter expertise that allowed for additional time for healthcare systems to prepare. Through the Special Pathogen Research Network, RESPTCs rapidly enrolled patients into early clinical trials. During periods of high community transmission, RESPTCs provided educational, clinical, and logistical support to a wide range of healthcare and nonhealthcare settings. In this article, we describe how NETEC and the RESPTC network leveraged this foundation of special pathogen readiness to strengthen the national healthcare system's response to the COVID-19 pandemic. NETEC and the RESPTC network have proven to be an effective model that can support the national response to future emerging special pathogens.

Prepared to Act: Lessons Learned by the Special Pathogens Research Network, Based on Collaborations with the NIAID-Led Adaptive COVID-19 Treatment Trial.

The need for well-controlled clinical trials is fundamental to advancing medicine. Care should be taken to maintain high standards in trial design and conduct even during emergency medical events such as an infectious disease outbreak. In 2020, SARS-CoV-2 emerged and rapidly impacted populations around the globe. The need for effective therapeutics was immediately evident, prompting the National Institutes of Health to initiate the Adaptive COVID-19 Treatment Trial. The Special Pathogens Research Network, made up of 10 Regional Emerging Special Pathogens Treatment Centers, was approached to participate in this trial and readily joined the trial on short notice. By trial closure, the Special Pathogens Research Network sites, making up 19% of all study sites, enrolled 26% of the total participants. The initial resources available and experience in running clinical trials at each treatment center varied from minimal experience and few staff to extensive experience and a large staff. Based on experiences during the first phase of this trial, the Special Pathogens Research Network members provided feedback regarding operational lessons learned and recommendations for conducting future studies during a pandemic. Communication, collaboration, information technology, regulatory processes, and access to resources were identified as important topics to address. Key stakeholders including institutions, institutional review boards, and study personnel must maintain routine communication to efficiently and effectively activate when future research needs arise. Regular and standardized training for new personnel will aid in transitions and project continuity, especially in a rapidly evolving environment. Trainings should include local just-in-time training for new staff and sponsor-designed modules to refresh current staff knowledge. We offer recommendations that can be used by institutions and sponsors to determine goals and needs when preparing to set up this type of trial for critical, short-notice needs.

Point-of-Care Lung Ultrasound Predicts Severe Disease and Death Due to COVID-19: A Prospective Cohort Study

OBJECTIVES: The clinical utility of point-of-care lung ultrasound (LUS) among hospitalized patients with COVID-19 is unclear. DESIGN: Prospective cohort study. SETTING: A large tertiary care center in Maryland, between April 2020 and September 2021. PATIENTS: Hospitalized adults (≥ 18 yr old) with positive severe acute respiratory syndrome coronavirus 2 reverse transcriptase-polymerase chain reaction results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were scanned using a standardized protocol including 12 lung zones and followed to determine clinical outcomes until hospital discharge and vital status at 28 days. Ultrasounds were independently reviewed for lung and pleural line artifacts and abnormalities, and the mean LUS Score (mLUSS) (ranging from 0 to 3) across lung zones was determined. The primary outcome was time to ICU-level care, defined as high-flow oxygen, noninvasive, or invasive mechanical ventilation, within 28 days of the initial ultrasound. Cox proportional hazards regression models adjusted for age and sex were fit for mLUSS and each ultrasound covariate. A total of 264 participants were enrolled in the study;the median age was 61 years and 114 participants (43.2%) were female. The median mLUSS was 1.0 (interquartile range, 0.5–1.3). Following enrollment, 27 participants (10.0%) went on to require ICU-level care, and 14 (5.3%) subsequently died by 28 days. Each increase in mLUSS at enrollment was associated with disease progression to ICU-level care (adjusted hazard ratio [aHR], 3.61;95% CI, 1.27–10.2) and 28-day mortality (aHR, 3.10;95% CI, 1.29–7.50). Pleural line abnormalities were independently associated with disease progression to death (aHR, 20.93;CI, 3.33–131.30). CONCLUSIONS: Participants with a mLUSS greater than or equal to 1 or pleural line changes on LUS had an increased likelihood of subsequent requirement of high-flow oxygen or greater. LUS is a promising tool for assessing risk of COVID-19 progression at the bedside.

IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.

BackgroundSome clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses initiated by the coronavirus SARS-CoV-2. We hypothesized autoantibodies against angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19 and are of mechanistic importance.MethodsIn an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM were analyzed via biolayer interferometry. Effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.ResultsAnti-ACE2 IgM (not IgG) autoantibodies were associated with severe COVID-19 and found in 18/66 (27.2%) patients with severe disease compared with 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; P = 0.0009). Anti-ACE2 IgM autoantibodies were rare (2/50) in non-COVID-19 ventilated patients with acute respiratory distress syndrome. Unexpectedly, ACE2-reactive IgM autoantibodies in COVID-19 did not undergo class-switching to IgG and had apparent KD values of 5.6-21.7 nM, indicating they are T cell independent. Anti-ACE2 IgMs activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting they contribute to the angiocentric pathology of COVID-19.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & Melinda Gates Foundation, Gates Philanthropy Partners, Donald B. and Dorothy L. Stabler Foundation, and Jerome L. Greene Foundation; NIH R01 AR073208, R01 AR069569, Institutional Research and Academic Career Development Award (5K12GM123914-03), National Heart, Lung, and Blood Institute R21HL145216, and Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Science Foundation Graduate Research Fellowship (DGE1746891).

Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology.

BACKGROUND: Several inflammatory cytokines are upregulated in severe coronavirus disease 2019 (COVID-19). We compared cytokines in COVID-19 versus influenza to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. METHODS: Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was used to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was used to identify cytokines that mediate the effect of BMI and age on disease severity. RESULTS: Interleukin-18 (IL-18), IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were significantly increased in COVID-19 versus influenza patients, whereas granulocyte macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN-λ1, IL-10, IL-15, and monocyte chemoattractant protein 2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not in severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. CONCLUSIONS: These findings point to activation of fundamentally different innate immune pathways in severe acute respiratory syndrome coronavirus 2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.

Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Delayed Rise of Oral Fluid Antibodies, Elevated BMI, and Absence of Early Fever Correlate With Longer Time to SARS-CoV-2 RNA Clearance in a Longitudinally Sampled Cohort of COVID-19 Outpatients.

BACKGROUND: Sustained molecular detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the upper respiratory tract (URT) in mild to moderate coronavirus disease 2019 (COVID-19) is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection. METHODS: Ninety-five symptomatic outpatients self-collected midturbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models. RESULTS: Viral RNA clearance, as measured by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR), in 507 URT samples occurred a median (interquartile range) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR-positive samples tested. All participants but 1 with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.92-0.99; P = .020) and body mass index (BMI) ≥25 kg/m2 (aHR, 0.37; 95% CI, 0.18-0.78; P = .009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as 1 of first 3 COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR, 2.06; 95% CI, 1.02-4.18; P = .044). CONCLUSIONS: We demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance.

Genomic diversity of SARS-CoV-2 during early introduction into the Baltimore-Washington metropolitan area.

The early COVID-19 pandemic was characterized by rapid global spread. In Maryland and Washington, DC, United States, more than 2500 cases were reported within 3 weeks of the first COVID-19 detection in March 2020. We aimed to use genomic sequencing to understand the initial spread of SARS-CoV-2 - the virus that causes COVID-19 - in the region. We analyzed 620 samples collected from the Johns Hopkins Health System during March 11-31, 2020, comprising 28.6% of the total cases in Maryland and Washington, DC. From these samples, we generated 114 complete viral genomes. Analysis of these genomes alongside a subsampling of over 1000 previously published sequences showed that the diversity in this region rivaled global SARS-CoV-2 genetic diversity at that time and that the sequences belong to all of the major globally circulating lineages, suggesting multiple introductions into the region. We also analyzed these regional SARS-CoV-2 genomes alongside detailed clinical metadata and found that clinically severe cases had viral genomes belonging to all major viral lineages. We conclude that efforts to control local spread of the virus were likely confounded by the number of introductions into the region early in the epidemic and the interconnectedness of the region as a whole.

Metabolic programs define dysfunctional immune responses in severe COVID-19 patients.

It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.

The Clinical Course of COVID-19 in the Outpatient Setting: A Prospective Cohort Study.

BACKGROUND: Outpatient coronavirus disease 2019 (COVID-19) has been insufficiently characterized. To determine the progression of disease and determinants of hospitalization, we conducted a prospective cohort study. METHODS: Outpatient adults with positive reverse transcription polymerase chain reaction results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited by phone between April 21 and July 23, 2020, after receiving outpatient or emergency department testing within a large health network in Maryland, United States. Symptoms were collected by participants on days 0, 3, 7, 14, 21, and 28, and portable pulse oximeter oxygen saturation (SaO2), heart rate, and temperature were collected for 15 consecutive days. Baseline demographics, comorbid conditions, and vital signs were evaluated for risk of subsequent hospitalization using negative binomial and logistic regression. RESULTS: Among 118 SARS-CoV-2-infected outpatients, the median age (interquartile range [IQR]) was 56.0 (50.0-63.0) years, and 50 (42.4%) were male. Among individuals in the first week of illness (n = 61), the most common symptoms included weakness/fatigue (65.7%), cough (58.8%), headache (45.6%), chills (38.2%), and anosmia (27.9%). Participants returned to their usual health a median (IQR) of 20 (13-38) days from symptom onset, and 66.0% of respondents were at their usual health during the fourth week of illness. Over 28 days, 10.9% presented to the emergency department and 7.6% required hospitalization. The area under the receiver operating characteristics curve for the initial home SaO2 for predicting subsequent hospitalization was 0.86 (95% CI, 0.73-0.99). CONCLUSIONS: Symptoms often persisted but uncommonly progressed to hospitalization among outpatients with COVID-19. Home SaO2 may be a helpful tool to stratify risk of hospitalization.

Metabolic programs define dysfunctional immune responses in severe COVID-19 patients.

It remains unclear why some patients infected with SARS-CoV-2 readily resolve infection while others develop severe disease. To address this question, we employed a novel assay to interrogate immune-metabolic programs of T cells and myeloid cells in severe and recovered COVID-19 patients. Using this approach, we identified a unique population of T cells expressing high H3K27me3 and the mitochondrial membrane protein voltage-dependent anion channel (VDAC), which were expanded in acutely ill COVID-19 patients and distinct from T cells found in patients infected with hepatitis c or influenza and in recovered COVID-19. Increased VDAC was associated with gene programs linked to mitochondrial dysfunction and apoptosis. High-resolution fluorescence and electron microscopy imaging of the cells revealed dysmorphic mitochondria and release of cytochrome c into the cytoplasm, indicative of apoptosis activation. The percentage of these cells was markedly increased in elderly patients and correlated with lymphopenia. Importantly, T cell apoptosis could be inhibited in vitro by targeting the oligomerization of VDAC or blocking caspase activity. In addition to these T cell findings, we also observed a robust population of Hexokinase II+ polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC), exclusively found in the acutely ill COVID-19 patients and not the other viral diseases. Finally, we revealed a unique population of monocytic MDSC (M-MDSC) expressing high levels of carnitine palmitoyltransferase 1a (CPT1a) and VDAC. The metabolic phenotype of these cells was not only highly specific to COVID-19 patients but the presence of these cells was able to distinguish severe from mild disease. Overall, the identification of these novel metabolic phenotypes not only provides insight into the dysfunctional immune response in acutely ill COVID-19 patients but also provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel metabolic therapeutic regimens.

National Action Plan for Expanding and Adapting the Healthcare System for the Duration of the COVID Pandemic

From the Executive Summary: The COVID-19 [coronavirus disease 2019] (COVID) pandemic has led to unprecedented action and innovation in the US healthcare system;at the same time, it has presented extraordinary challenges and risks. Through dramatic augmentation of surge capacity, deferral of other services, and implementation of crisis standards of care, hospitals in many locations have been able to absorb the blow of the first peak of COVID cases and continue to provide lifesaving care to both COVID patients and others with life-threatening emergencies. But many communities are just beginning to experience the full force of the pandemic, and in every location, the healthcare response to COVID has come at a very dear price. Healthcare facilities have sustained huge financial losses, and healthcare workers' health and well-being have been put at high risk. New standard operating procedures and work processes have been improvised, and many old lessons have had to be relearned.COVID-19 (Disease);Epidemics