Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial.

PURPOSE: Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its' optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock. METHODS: In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days. RESULTS: Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59-83] vs 94 h [IQR 74-141]; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration. CONCLUSION: In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.

Angiotensin II - A Brief Review and Role in Severe SARS-COV-2 Sepsis.

The renin-angiotensin-aldosterone system (RAAS), whose major vasopressor effector is angiotensin II (ATII), has multiple activities and regulates sodium-water homeostasis and fluid and blood pressure homeostasis. RAAS plays a crucial role in cardiocirculatory shock because it counteracts hypotension and hypovolemia by activating different physiologic responses. Based on the encouraging results of the ATHOS-3 trial, the US Food and Drug Administration and the European Medicines Agency approved the use of ATII for catecholamine-resistant vasodilatory shock. More recently, ATII was used for the compassionate treatment of critically ill patients with COVID-19. Beyond its vasopressor properties, ATII was hypothesized to have antiviral activity because it induces internalization and degradation of angiotensin-converting enzyme 2 receptors used by SARS-Cov-2 to infect cells. Overall, the use of ATII in patients with COVID-19 showed promising results because its administration was associated with the achievement and maintenance of target mean arterial pressure, increased PaO2/FIO2 ratio, and decreased FIO2. The aim of this narrative review is to summarize the available knowledge on the use of ATII in patients with COVID-19.

Initial evaluation of extracorporeal immunomodulatory therapy for the treatment of critically ill COVID-19 infected patients.

Severe COVID-19 infection results in significant immune dysregulation resulting from excessive recruitment and activation of neutrophils. The aim of this study was to confirm feasibility, initial safety and detect signal of efficacy of a non-propriety device delivered using an intermittent extra-corporeal system (LMOD) allowing leucocytes modulation in the setting of Severe COVID-19 infection. Twelve patients were recruited. Inclusion criteria were > 18 years age, confirmed COVID-19, acute respiratory distress syndrome requiring mechanical support and hypotension requiring vasopressor support. Primary end point was vasopressor requirements (expressed as epinephrine dose equivalents) and principle secondary endpoints related to safety, ability to deliver the therapy and markers of inflammation assessed over five days after treatment initiation. LMOD treatment appeared safe, defined by hemodynamic stability and no evidence of white cell number depletion from blood. We demonstrated a significant decrease in vasopressor doses (-37%, p = 0.02) in patients receiving LMOD therapy (despite these patients having to tolerate an additional extracorporeal intermittent therapy). Vasopressor requirements unchanged/increasing in control group (+ 10%, p = 0.48). Although much about the use of this therapy in the setting of severe COVID-19 infection remains to be defined (e.g. optimal dose and duration), this preliminary study supports the further evaluation of this novel extracorporeal approach.

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Clinical Trends Among U.S. Adults Hospitalized With COVID-19, March to December 2020 : A Cross-Sectional Study.

BACKGROUND: The COVID-19 pandemic has caused substantial morbidity and mortality. OBJECTIVE: To describe monthly clinical trends among adults hospitalized with COVID-19. DESIGN: Pooled cross-sectional study. SETTING: 99 counties in 14 states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET). PATIENTS: U.S. adults (aged ≥18 years) hospitalized with laboratory-confirmed COVID-19 during 1 March to 31 December 2020. MEASUREMENTS: Monthly hospitalizations, intensive care unit (ICU) admissions, and in-hospital death rates per 100 000 persons in the population; monthly trends in weighted percentages of interventions, including ICU admission, mechanical ventilation, and vasopressor use, among an age- and site-stratified random sample of hospitalized case patients. RESULTS: Among 116 743 hospitalized adults with COVID-19, the median age was 62 years, 50.7% were male, and 40.8% were non-Hispanic White. Monthly rates of hospitalization (105.3 per 100 000 persons), ICU admission (20.2 per 100 000 persons), and death (11.7 per 100 000 persons) peaked during December 2020. Rates of all 3 outcomes were highest among adults aged 65 years or older, males, and Hispanic or non-Hispanic Black persons. Among 18 508 sampled hospitalized adults, use of remdesivir and systemic corticosteroids increased from 1.7% and 18.9%, respectively, in March to 53.8% and 74.2%, respectively, in December. Frequency of ICU admission, mechanical ventilation, and vasopressor use decreased from March (37.8%, 27.8%, and 22.7%, respectively) to December (20.5%, 12.3%, and 12.8%, respectively); use of noninvasive respiratory support increased from March to December. LIMITATION: COVID-NET covers approximately 10% of the U.S. population; findings may not be generalizable to the entire country. CONCLUSION: Rates of COVID-19-associated hospitalization, ICU admission, and death were highest in December 2020, corresponding with the third peak of the U.S. pandemic. The frequency of intensive interventions for management of hospitalized patients decreased over time. These data provide a longitudinal assessment of clinical trends among adults hospitalized with COVID-19 before widespread implementation of COVID-19 vaccines. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

The critical care literature 2020.

Given the dramatic increase in critically ill patients who present to the emergency department for care, along with the persistence of boarding of critically ill patients, it is imperative for the emergency physician to be knowledgeable about recent developments in resuscitation and critical care medicine. This review summarizes important articles published in 2020 that pertain to the resuscitation and care of select critically ill patients. These articles have been selected based on the authors annual review of key critical care, emergency medicine and medicine journals and their opinion of the importance of study findings as it pertains to the care of critically ill ED patients. Several key findings from the studies discussed in this paper include the administration of dexamethasone to patients with COVID-19 infection who require mechanical ventilation or supplemental oxygen, the use of lower levels of positive end-expiratory pressure for patients without acute respiratory distress syndrome, and early initiation of extracorporeal membrane oxygenation for out-of-hospital cardiac arrest patients with refractory ventricular fibrillation if resources are available. Furthermore, the emergency physician should not administer tranexamic acid to patients with acute gastrointestinal bleeding or administer the combination of vitamin C, thiamine, and hydrocortisone for patients with septic shock. Finally, the emergency physician should titrate vasopressor medications to more closely match a patient's chronic perfusion pressure rather than target a mean arterial blood pressure of 65 mmHg for all critically ill patients.

Multisystem Inflammatory Syndrome in Children: Survey of Protocols for Early Hospital Evaluation and Management.

OBJECTIVE: To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the US. STUDY DESIGN: We conducted a cross-sectional survey from June 16 to July 16, 2020, of US children's hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which ≤5 patients had been treated. RESULTS: In all, 40 centers of varying size and experience with MIS-C participated in this protocol survey. Overall, 21 of 40 centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely recommended medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols primarily for moderate or severe cases. Aspirin was commonly recommended for mild cases, whereas heparin or low molecular weight heparin were to be used primarily in severe cases. In severe cases, anakinra and vasopressors frequently were recommended; 39 of 40 centers recommended follow-up with cardiology. There were similar findings between centers in which >5 patients vs ≤5 patients had been managed. Supplemental materials containing hospital protocols are provided. CONCLUSIONS: There are many similarities yet key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C.

Characterisation and outcomes of ARDS secondary to pneumonia in patients with and without SARS-CoV-2: a single-centre experience.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is the major cause of mortality in patients with SARS-CoV-2 pneumonia. It appears that development of 'cytokine storm' in patients with SARS-CoV-2 pneumonia precipitates progression to ARDS. However, severity scores on admission do not predict severity or mortality in patients with SARS-CoV-2 pneumonia. Our objective was to determine whether patients with SARS-CoV-2 ARDS are clinically distinct, therefore requiring alternative management strategies, compared with other patients with ARDS. We report a single-centre retrospective study comparing the characteristics and outcomes of patients with ARDS with and without SARS-CoV-2. METHODS: Two intensive care unit (ICU) cohorts of patients at the Queen Elizabeth Hospital Birmingham were analysed: SARS-CoV-2 patients admitted between 11 March and 21 April 2020 and all patients with community-acquired pneumonia (CAP) from bacterial or viral infection who developed ARDS between 1 January 2017 and 1 November 2019. All data were routinely collected on the hospital's electronic patient records. RESULTS: A greater proportion of SARS-CoV-2 patients were from an Asian ethnic group (p=0.002). SARS-CoV-2 patients had lower circulating leucocytes, neutrophils and monocytes (p<0.0001), but higher CRP (p=0.016) on ICU admission. SARS-CoV-2 patients required a longer duration of mechanical ventilation (p=0.01), but had lower vasopressor requirements (p=0.016). DISCUSSION: The clinical syndromes and respiratory mechanics of SARS-CoV-2 and CAP-ARDS are broadly similar. However, SARS-CoV-2 patients initially have a lower requirement for vasopressor support, fewer circulating leukocytes and require prolonged ventilation support. Further studies are required to determine whether the dysregulated inflammation observed in SARS-CoV-2 ARDS may contribute to the increased duration of respiratory failure.

Angiotensin II Administration in Patients With COVID-19 Shock.

PURPOSE: To understand the hemodynamic effect of angiotensin II as a vasopressor in patients with shock secondary to COVID-19 infection. METHODS: A retrospective analysis was performed on all patients at a single center with COVID-19 infection and shock who were treated with angiotensin II. The hemodynamic response to angiotensin II was estimated by recording the mean arterial pressure, norepinephrine equivalent dose (NED) and urine output. RESULTS: Ten patients with COVID-19 related shock were treated with angiotensin II. Over the initial 6 hours, the average the NED decreased by 30.4% (from 64.6 to 44 µg/min) without a significant change in the mean arterial pressure (0.7% decrease). Six patients experienced at least a 25% reduction in NED by 6 hours, and 2 experienced at least a 50% reduction. CONCLUSIONS: On average, the hemodynamic response to angiotensin II in COVID-19 related shock was favorable. Two patients had a marked rapid improvement. Given the relationship of SARS-CoV-2 with the renin-angiotensin-aldosterone system, further evaluation of angiotensin II for the treatment of COVID-19 related shock is warranted.

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19.

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

Characteristics and comparative clinical outcomes of prisoner versus non-prisoner populations hospitalized with COVID-19.

Prisons in the United States have become a hotbed for spreading COVID-19 among incarcerated individuals. COVID-19 cases among prisoners are on the rise, with more than 143,000 confirmed cases to date. However, there is paucity of data addressing clinical outcomes and mortality in prisoners hospitalized with COVID-19. An observational study of all patients hospitalized with COVID-19 between March 10 and May 10, 2020 at two Henry Ford Health System hospitals in Michigan. Clinical outcomes were compared amongst hospitalized prisoners and non-prisoner patients. The primary outcomes were intubation rates, in-hospital mortality, and 30-day mortality. Multivariable logistic regression and Cox-regression models were used to investigate primary outcomes. Of the 706 hospitalized COVID-19 patients (mean age 66.7 ± 16.1 years, 57% males, and 44% black), 108 were prisoners and 598 were non-prisoners. Compared to non-prisoners, prisoners were more likely to present with fever, tachypnea, hypoxemia, and markedly elevated inflammatory markers. Prisoners were more commonly admitted to the intensive care unit (ICU) (26.9% vs. 18.7%), required vasopressors (24.1% vs. 9.9%), and intubated (25.0% vs. 15.2%). Prisoners had higher unadjusted inpatient mortality (29.6% vs. 20.1%) and 30-day mortality (34.3% vs. 24.6%). In the adjusted models, prisoner status was associated with higher in-hospital death (odds ratio, 2.32; 95% confidence interval (CI), 1.33 to 4.05) and 30-day mortality (hazard ratio, 2.00; 95% CI, 1.33 to 3.00). In this cohort of hospitalized COVID-19 patients, prisoner status was associated with more severe clinical presentation, higher rates of ICU admissions, vasopressors requirement, intubation, in-hospital mortality, and 30-day mortality.

Effects of COVID-19 on in-hospital cardiac arrest: incidence, causes, and outcome - a retrospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), an emerging virus, has caused a global pandemic. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has led to high hospitalization rates worldwide. Little is known about the occurrence of in-hospital cardiac arrest (IHCA) and high mortality rates have been proposed. The aim of this study was to investigate the incidence, characteristics and outcome of IHCA during the pandemic in comparison to an earlier period. METHODS: This was a retrospective analysis of data prospectively recorded during 3-month-periods 2019 and 2020 at the University Medical Centre Hamburg-Eppendorf (Germany). All consecutive adult patients with IHCA were included. Clinical parameters, neurological outcomes and organ failure/support were assessed. RESULTS: During the study period hospital admissions declined from 18,262 (2019) to 13,994 (2020) (- 23%). The IHCA incidence increased from 4.6 (2019: 84 IHCA cases) to 6.6 (2020: 93 IHCA cases)/1000 hospital admissions. Median stay before IHCA was 4 (1-9) days. Demographic characteristics were comparable in both periods. IHCA location shifted towards the ICU (56% vs 37%, p < 0.01); shockable rhythm (VT/VF) (18% vs 29%, p = 0.05) and defibrillation were more frequent in the pandemic period (20% vs 35%, p < 0.05). Resuscitation times, rates of ROSC and post-CA characteristics were comparable in both periods. The severity of illness (SAPS II/SOFA), frequency of mechanical ventilation and frequency of vasopressor therapy after IHCA were higher during the 2020 period. Overall, 43 patients (12 with & 31 without COVID-19), presented with respiratory failure at the time of IHCA. The Horowitz index and resuscitation time were significantly lower in patients with COVID-19 (each p < 0.01). Favourable outcomes were observed in 42 and 10% of patients with and without COVID-19-related respiratory failure, respectively. CONCLUSION: Hospital admissions declined during the pandemic, but a higher incidence of IHCA was observed. IHCA in patients with COVID-19 was a common finding. Compared to patients with non-COVID-19-related respiratory failure, the outcome was improved.

High lipasemia is frequent in Covid-19 associated acute respiratory distress syndrome.

BACKGROUND: Covid-19 is a rapidly spreading viral disease that can cause severe acute respiratory distress syndrome (ARDS). Besides the lungs it can also affect other organs like the heart or the liver. Whether there is a pancreatic manifestation as well is currently unclear. METHODS: and aims: We prospectively collected patient information of patients with Covid-19 associated ARDS in a registry (COvid Registry REChts der Isar intensive care Trial - CORRECT) and analyzed this patient cohort for signs of acute pancreatitis (e.g. lipase activity >3 times the upper limit). RESULTS: 12/38 (31.6%) patients with Covid-19 associated ARDS had a serum lipase activity >180 U/l. Median lipase activity was 422 U/l (186-1127). No patient showed typical findings of acute pancreatitis on imaging studies. On hemodynamic monitoring no patient had signs of intravascular fluid demand regarding MAP, GEDVI and therapy with vasopressors. To avoid worsening respiratory function no treatment with crystalloids was initiated. Lipasemia was not explained by gastroenteritis or renal insufficiency, occurred before as well as after viral clearance and 16.1 ± 6.0 days after the first symptoms. No patient developed severe acute pancreatitis during the follow up period of 35.8 ± 8.3 days. CONCLUSION: High lipasemia without typical signs of acute pancreatitis is a frequent finding in severe Covid-19 associated ARDS. Considering the markedly high levels of serum lipase activity, we think impaired microcirculation in severely ill patients can explain this finding rather than extra-pancreatic co-morbidities (UTN: DRKS00021612).

Outcomes of COVID-19 Among Hospitalized Health Care Workers in North America.

Importance: Although health care workers (HCWs) are at higher risk of acquiring coronavirus disease 2019 (COVID-19), it is unclear whether they are at risk of poorer outcomes. Objective: To evaluate the association between HCW status and outcomes among patients hospitalized with COVID-19. Design, Setting, and Participants: This retrospective, observational cohort study included consecutive adult patients hospitalized with a diagnosis of laboratory-confirmed COVID-19 across 36 North American centers from April 15 to June 5, 2020. Data were collected from 1992 patients. Data were analyzed from September 10 to October 1, 2020. Exposures: Data on patient baseline characteristics, comorbidities, presenting symptoms, treatments, and outcomes were collected, including HCW status. Main Outcomes and Measures: The primary outcome was a requirement for mechanical ventilation or death. Multivariable logistic regression was performed to yield adjusted odds ratios (AORs) and 95% CIs for the association between HCW status and COVID-19-related outcomes in a 3:1 propensity score-matched cohort, adjusting for residual confounding after matching. Results: In total, 1790 patients were included, comprising 127 HCWs and 1663 non-HCWs. After 3:1 propensity score matching, 122 HCWs were matched to 366 non-HCWs. Women comprised 71 (58.2%) of matched HCWs and 214 (58.5%) of matched non-HCWs. Matched HCWs had a mean (SD) age of 52 (13) years, whereas matched non-HCWs had a mean (SD) age of 57 (17) years. In the matched cohort, the odds of the primary outcome, mechanical ventilation or death, were not significantly different for HCWs compared with non-HCWs (AOR, 0.60; 95% CI, 0.34-1.04). The HCWs were less likely to require admission to an intensive care unit (AOR, 0.56; 95% CI, 0.34-0.92) and were also less likely to require an admission of 7 days or longer (AOR, 0.53; 95% CI, 0.34-0.83). There were no differences between matched HCWs and non-HCWs in terms of mechanical ventilation (AOR, 0.66; 95% CI, 0.37-1.17), death (AOR, 0.47; 95% CI, 0.18-1.27), or vasopressor requirements (AOR, 0.68; 95% CI, 0.37-1.24). Conclusions and Relevance: In this propensity score-matched multicenter cohort study, HCW status was not associated with poorer outcomes among hospitalized patients with COVID-19 and, in fact, was associated with a shorter length of hospitalization and decreased likelihood of intensive care unit admission. Further research is needed to elucidate the proportion of HCW infections acquired in the workplace and to assess whether HCW type is associated with outcomes.

The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection.

Background: The majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency. Methods: We summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19. Results: High percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 µg/dl, which met the criteria for the diagnosis of CIRCI. Conclusion: We demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.